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Host cytokine response and resistance to Salmonella infection
Microbes and Infection, 1, 1999, 719−726 © Elsevier, Paris
Review
Host cytokine response and resistance to Salmonella infection Anne-Christine Lalmanach*, Frédéric Lantier Institut national de la recherche agronomique, Centre de recherche de Tours, Laboratoire de pathologie infectieuse et immunologie, Nouzilly, France
ABSTRACT – Knowledge of the host response, of the resistance process, and of the mediators committed against Salmonella infection is essential to progress towards better means of prophylaxis and eradication. In this context, the present contribution attempts to interconnect, with the pivotal role of the macrophage, the early resistance process under the control of the Nramp1 gene and the cytokine response for resolving infection. IL-12 produced by macrophages is an inducer of IFN-γ production, which in turn activates the macrophage antibacterial activity and synergizes its effects with TNF-α. All three of these cytokines are powerful actors in the first line of anti-Salmonella defence. It can be pointed out that susceptible and resistant individuals do not seem to see the cytokine environment the same way, the former being unresponsive to IL-1 or GM-CSF treatment and deficient in IFN-γ production. These discrepancies may rely on cell signalling events that could be defective in macrophages of the susceptible phenotype. © Elsevier, Paris cytokines / disease-susceptibility – genetics / natural immunity / macrophages / Salmonella infections – animal
1. Introduction Invasive Salmonella species are causative agents of several gastrointestinal diseases and are responsible for enteric fevers in humans and several animal species. Salmonellae are still widespread enough to provoke typhoid fever or frequent cases of food poisoning, thus remaining a pathogen of interest in human health. Since Salmonella may be present in animals or products of animal origin, this bacterium represents a target pathogen for worldwide epidemiological surveillance and development of new means of eradication [1]. An undoubted way to control the spread of Salmonella is to reinforce the immune response of the host against this Gram-negative and facultative intracellular bacteria. Many cytokines possess the capacity to orchestrate immune cell migration, proliferation, activation, and interactions, which can culminate in antibacterial activity, and much information concerning the crucial role of the cytokines in host defence against infecting microorganisms is available (see [2] and [3] for review). Cytokines involved in resistance to infectious agents are of major importance when considering therapeutic plans and vaccine strategies. Some cytokines have already been used as adjuvants in vaccine design (see [4] for review) in order to boost the immune response. * Correspondence and reprints Microbes and Infection 1999, 719-726
The present review attempts to summarise recent data concerning the involvement of cytokines during the course of Salmonella infection. After presenting the elements of the immune response through the study of acquired and innate anti-Salmonella immunity, we will focus on the recent advances in research on cytokine response to Salmonella and its relationship with the resistance feature of the host.
2. Host immune response to Salmonella infection The immune response to primary Salmonella infection has been extensively studied (reviewed in [5] and [6]). The course of a sublethal challenge consists of i) rapid clearance of a large fraction of the inoculum; ii) early exponential growth of the remaining bacteria in the reticuloendothelial system (RES), mainly in mononuclear cells and in polymorphonuclear leucocytes; iii) suppression of the bacterial exponential growth in the RES, resulting in a plateau phase, in which macrophages and natural killer (NK) cells are the probable effector cells, with interferon (IFN)-γ and tumour necrosis factor (TNF)-α as mediators; and iv) clearance of the microorganisms from the tissues, which requires specific T-cell-dependent and major histocompatibility complex (MHC)-controlled immune mechanisms. 719
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In large animal species, such as sheep or cattle, it is possible to examine in detail the immune response induced in the lymph node draining the site of Salmonella inoculation by histological analysis or by a lymph cannulation technique, which allows a dynamic study of the immune response in vivo. It has thus been shown that both humoral and cellular responses are induced with the observation of a massive infiltration of polymorphonuclear leucocytes followed by lymphoid hyperplasia with prominent germinal centres [7]. The measure of the cell output in the efferent lymph reveals an important B lymphoblast export associated with an increase in antibody titres and an increase, 4 to 6 days postinoculation, in interleukin (IL)-1, TNF-α, IL-2, IFN-γ, and IL-4 mRNAs of efferent lymph cells [8]. The mechanism of long-term protection, which involves a specific recall of immunity (see [5] for review), is still highly disputed, probably because it depends on the host-parasite combinations, on the degree of Salmonella virulence, and on the innate resistance or susceptibility of the host. However, it has finally been shown that both humoral and cellular immunity is conferred by live vaccine immunization [9], which offers optimal protection in susceptible hosts [10]. Killed vaccines are only protective for innately resistant hosts, probably because they cannot induce cellular but only humoral responses [11].
3. Natural resistance to Salmonella infection: innate immunity Several mouse genes affecting resistance to primary invasive Salmonella infections have been more or less characterized (see [12] for review): among these are the genes Ity, for immunity to Salmonella typhimurium, Xid, for X-linked immunodeficiency, Nu, for nude gene, which is a pleiotropic mutation inducing a hairless phenotype and an impairment of T-cell development, and Lps, for response to bacterial lipopolysacharide. A role for MHCassociated genes and for as yet nonidentified ones on mouse chromosomes has also been reported. The survival of animals during the first phase of infection, before the development of specific acquired immunity, depends on their natural resistance, which controls the early exponential growth of Salmonellae in macrophages of the RES. This natural or innate resistance is under genetic control of the Nramp1 (for natural resistance-associated macrophage protein) gene of the Ity/Lsh/Bcg locus on chromosome 1, which regulates the growth of the intracellular pathogens S. typhimurium, Leishmania donovani, and Mycobacterium bovis, respectively (see [13] for review). A mutated allele of this gene determines the susceptibility to infection with several intracellular pathogens. In vitro, Nramp1 gene expression can be induced in mouse macrophage cell lines by IFN-γ and LPS treatment, which is equally efficient on macrophages in vivo after intraperitoneal injection [14]. Nramp1 has also been recently described in different species of domestic animals [15-17]. However, even if the structure of the Nramp1 gene product has been well characterized as a membrane protein closely related to the 720
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family of cation transporters, its precise function remains unknown, and its precise role in the mechanism underlying the resistant phenotype has not been elucidated so far. Although they have not yet been fully identified as genes of resistance to Salmonella infection, cytokine genes and cytokine receptor genes should also be considered as such. We have already predicted that in the near future a number of polymorphisms in cytokine genes will be identified, and that a number of them will be associated with susceptibility to infection, while genetic analysis of susceptibility to infection will increase in outbred populations, in humans, and domestic animals as well [18]. In fact, a mutation of the IL-12 receptor has recently been associated with severe susceptibility to Salmonella and to mycobacterial infections in humans [19].
4. Cytokines in response to Salmonella infection The severity and outcome of Salmonella infections are determined by multiple bacterial and host factors. Cytokines are key regulators of the host response to intracellular pathogens (see [3] for review). Various bacterial products from Salmonella are potent inducers of cytokine expression by immune cells [20-22]. Effector cells for Nramp1 genotype expression being macrophages, cytokines which can activate macrophages most likely contribute to the early resistance process. Furthermore, cytokines produced by macrophages and capable of triggering and/or enhancing an antibacterial immune response must be potent protagonists of the antiSalmonella defence (figure 1). Therefore, we will focus our analysis on the results concerning cytokines active on or produced by these cells and with known antiinfectious function. The role of IFN-γ, IL-12, TNF-α and IL-1 will thus be discussed in light of the recent literature, and the discussion will be extended to other cytokines, such as IL-4, GM-CSF, IL-6, and IL-10. The involvement of these cytokines in the resistant phenotype of infected individuals and consequently in the early resistance process will be analysed. This early cytokine response can probably condition the orientation of the subsequent T-cell response towards the type-1 or type-2 pattern of cytokine secretion described (see [23] and [24] for review). Essentially, the type-1 cytokine response is needed to resolve infection by various intracellular pathogens. This has been particularly well documented using experimental cutaneous Leishmania infection. However, the situation is not so clear-cut in the case of cytokine response to Salmonella. Very recent data demonstrate a predominant type-1 T-cell response (IL-2 and IFN-γ) to a recombinant Salmonella vaccine strain in mice carrying the Nramp1 gene resistant allele, associated with enhanced resolution of challenge infection with Leishmania, while Nramp1s mice mount a type-2 response (IL-4) and show exacerbated lesion growth upon challenge [25]. Another recent study has shown a disregulation of the type-1/type-2 balance in C57BL/6 mice with the beige mutation during Salmonella choleraesuis infection, manifested by an overproduction Microbes and Infection 1999, 719-726
Cytokine response and salmonellosis
Review
Figure 1. Cytokines, signals, and resistance to Salmonella infection: an overview of the early central role of the macrophage. Mononuclear phagocytes encountering bacteria or bacterial products such as lipopolysaccharide (LPS) can be triggered to react efficiently against the infectious process, especially if they harbour the resistant allele of the Nramp1 gene. This efficient reaction, beginning with phagocytosis, can be mediated by means of expression of various genes, such as cytokine genes (IL-1, IL-6, TNF-α or IL-12), involved in antigen presentation (MHC class II), or in bactericidal function (inducible nitric oxide synthase (iNOS)). The expression of such genes culminates in antiinfectious activity of the macrophage with the help of IFN-γ produced by NK cells and/or T cells and is connected with the acquired and cognate immune response mediated by T and B cells according to the helper T cell (TH) commitment type. Macrophage activation can be negatively regulated by IL-10 from type-2 TH cells (TH2).
of IL-4 associated with increased susceptibility compared with normal C57BL/6 mice, which produce mainly IFN-γ and are more resistant [26]. 4.1. IFN-γ
As a major candidate for enhancing macrophage antibacterial activity, IFN-γ has been extensively studied in salmonellosis, and IFN-γ involvement in resistance to Salmonella infection during the first week is well documented. IFN-γ is induced during the initial step of infection, since elevated levels of IFN-γ mRNA are found very early in the gut-associated lymphoid tissue and spleen of mice orally challenged with S. typhimurium [27]. Elevated levels of plasma IFN-γ have been recorded at day 3 postintraperitoneal infection with the same Salmonella serotype [28]. In vitro IFN-γ production by lymphocytes from human volunteers orally immunized with attenuated Salmonella typhi vaccines is also increased in response to antigen stimulation [29]. Systemic administration of this cytokine during the first few days after challenge with a virulent strain reduces the Microbes and Infection 1999, 719-726
severity of Salmonella infection in mice [30, 31] and rats [32]. Controversial results have shown the inability of recombinant IFN-γ (rIFN-γ) to activate in vitro or in vivo antibacterial activity of mouse peritoneal macrophages [33], while another study has demonstrated the enhanced Salmonella killing activity in rIFN-γ-activated macrophages in vitro [34]. The depletion of the cytokine by anti-IFN-γ treatment increases dramatically the severity of the disease [30], which is further amplified with concomitant treatment with anti-TNF-α antibody [35, 36]. Furthermore, mice unresponsive to IFN-γ (IFN-γR -/-) are highly susceptible to S. typhimurium aroA– infection [37]. Elsewhere, when comparing the responses of genetically resistant and susceptible mouse strains to Salmonella infection, the results are contradictory. Two studies have revealed no IFN-γmRNA production deficiency associated with susceptibility to Salmonella spp. [38, 39]. Others have suggested that early resistance of Nramp1r mice is partly attributable to their capacity to produce IFN-γ after infection [40], whereas susceptible (Nramp1s) mice fail to produce normal amounts of IFN-γ on the basis of in vitro 721
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experiments [41, 42]. Nevertheless, although it has not been reported in the case of salmonellosis, severe human mycobacterial infections can be associated with IFN-γ receptor gene deficiencies, which demonstrates the major role of this cytokine in resistance to intracellular pathogens [43]. The IFN-γ-producing cells during the first week of Salmonella infection are unlikely to be T lymphocytes, since depletion of these cells at this stage does not lead to major reduction of IFN-γ secretion [35]. Another study has reported the essential role of NK cells, and indirectly macrophages, in IFN-γ production by murine splenocytes after in vitro stimulation with S. typhimurium [41]. IL-18 is an inducer of IFN-γ production by NK cells and has recently been shown to mediate protection against Salmonella infection [44]. IL-12, a cytokine produced by macrophages, can also induce IFN-γ secretion by NK cells [45, 46]. These findings have thus prompted different groups to study the involvement of IL-12 in resistance to salmonellosis. 4.2. Il-12
The role of IL-12 as a proximal stimulator of IFN-γ release during endotoxemia has been reported [47]. Recent work has shown the important role of IL-12 in resistance to Salmonella infection. Following oral inoculation, Salmonella sp. induces IL-12 production at mucosal sites and in mesenteric lymph nodes [48, 49]. Furthermore, IL-12 neutralization with monoclonal antibodies reveals an IL-12-dependent mechanism of resistance in primary and secondary infections [49, 50]. Macrophages seem to be the cells responsible for IL-12 secretion upon vaccination with live Salmonella spp., and the protection efficiency is correlated with an increased production of IL-12 mRNA [51], although the major form secreted is the p40 subunit and not the complete bioactive 70-kDa form of IL-12 [52]. Elsewhere, the kinetics and magnitude of IL-12 mRNA expression in Nramp1s and Nramp1r mice following a Salmonella challenge are similar, thus demonstrating that IL-12 response is not essential in the expression of the resistant phenotype [38]. However, it has recently been reported that IL-12 receptor-deficient patients are highly susceptible and develop a severe Salmonella infection [19]. Finally, another recent work on a murine model of infection with an attenuated aroA Salmonella strain has shown that IL-12 neutralization induced a higher bacterial load in liver and spleen, associated with an infiltration of mononuclear cells instead of granuloma formation, and with reduced IFN-γ production, MHC class II antigen expression, and nitric oxide synthase activity. These impairments of host resistance means could be restored by administration of rIFN-γ to anti-IL-12-treated mice. These data are a major clue in the decisive interconnection between IL-12 and IFN-γ and their role in the restriction of Salmonella infection [53]. 4.3. IL-1 and TNF-α
The cytokines IL-1 and TNF-α are intimately associated in the mechanism of inflammation and the response to infectious agents. They have been implicated in the pathogenesis of sepsis caused by Gram-negative microorgan722
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isms [54]. These cytokines can synergize their activities and have been shown to be required for IL-12-induced development of type-1 T helper cells in BALB/c Nramp1s mice [55]. TNF-α production during salmonellosis remains controversial. Systemic TNF-α release in response to Salmonella infection has not been detected in mice [28] or even in the case of severe septicaemic salmonellosis in calves [56]. In these species, the TNF-α level seems to rise only in response to endotoxin or LPS injection. Nevertheless, an increase in the serum level of TNF-α has been measured after intraperitoneal challenge with S. typhimurium in mice [57] or in patients with typhoid fever [58]. In vitro, human promonocytic cell lines produce TNF-α in response to different Salmonella serotypes or in response to their released product [59]. TNF-α could play an important role in host defence against salmonellosis through its cytotoxic activity against Salmonella sp.-infected cells [60], although this cytotoxic effect was measured on fibroblasts, which are not the usual host target cells where salmonellae reside in vivo. Exogenous TNF-α can increase resistance to S. typhimurium infection [61], although data have shown that this increased survival after TNF-α treatment seems to be restricted to mice of the resistant phenotype [62]. Endogenous TNF-α production plays a role in the host response to the same Salmonella strain, since the administration of anti-TNF-α antibodies decreased resistance to infection [35, 63] by abolishing the plateau phase [64] and the concomitant and related granuloma formation in the RES [65]. TNF-α is also important in the specific recall of immunity to virulent salmonella conferred by immunization with live vaccines [66]. TNF-α receptor p55-deficient mice have been shown to succumb earlier to virulent S. typhimurium challenge and were not protected by an aroA– vaccine strain against the virulent strain [67]. TNF-α seems to be constantly required for the control of virulent salmonella in the RES, in both a sublethal primary infection in innately resistant mice and also in a secondary infection in innately susceptible mice immunized with a live vaccine [68]. IL-1 is also produced by macrophages in vitro, when primed by Salmonella infection in vivo [40]. Serum IL-1 level remains very low after S. typhimurium infection in mice, but these results have been obtained with Nramp1s mice only [57]. However, Salmonella dublin infection in both Nramp1r and Nramp1s mice is characterized by an increased expression of IL-1α mRNAs among other cytokines mRNAs [38]. IL-1 administration to mice increases the host resistance, although large variations in the response can be obtained according to the mouse strain studied: globally, IL-1 treatment is only beneficial prior to Salmonella infection in Nramp1r mice and after infection in Nramp1r Lpsd mice, but has no effect in Nramp1s mice [62, 69, 70]. Finally, TNF-α and IL-1 responses, which are associated with mouse survival in Salmonella infection, are not directly incriminated in the immune deficiency of mice of the Nramp1s phenotype, since the kinetics and magnitude of response of both cytokines are similar in innately susceptible and resistant mice [38]. Microbes and Infection 1999, 719-726
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4.4. Other cytokines
Among the cytokines capable of eliciting macrophage activation and microbicidal activity, GM-CSF is a good candidate. During the initial step of infection, within a few hours, Salmonella attachment to macrophages in vitro increases production of GM-CSF as well as IL-1β and IL-6 mRNAs [71]. GM-CSF mRNA expression is also increased in vivo in spleen and liver within a few days following Salmonella infection but does not differ between susceptible and resistant mouse strains [38], although exogenous GM-CSF given during the course of a lethal Salmonella infection raises the survival of Nramp1r but not Nramp1s mice [72]. IL-4 is a mediator capable of directing helper T-cell precursor into a type-2 T helper cell differentiation in vitro and of changing orientation of the immune response towards type-2-induced humoral immunity (see [23] for review). IL-4 mRNA expression does not seem to be increased in response to virulent Salmonella infection in vivo [38]. However, if an IL-4 expression system is introduced into a live S. typhimurium vaccine vector, this generates higher growth and survival of Salmonella in BALB/c mice, with a noticeable alteration in macrophage killing activity in vitro [73]. Furthermore, increased killing and abcess development is observed in mice harbouring the wild-type IL-4 gene (IL-4 +/+) challenged with an S. typhimurium purE derivative than in mice harbouring the null allele (IL-4 -/-), even if both mouse groups exhibit a type-1 T-cell immune response [74]. Finally, multiple evidence tends to suggest that IL-4 has a deleterious effect on the host ability to protect against Salmonella spp. IL-6 was initially described as a B-cell terminal differentiation inducer. Besides being a component of the inflammatory response, IL-6 has been shown to play an important role in the mucosal antibody response in vivo [75]. Some evidence suggested a potent role for IL-6 in anti-Salmonella defence: i) patients suffering from typhoid fever present elevated IL-6 levels in the serum [58]; ii) IL-6 secretion by peripheral blood mononuclear cells of volunteers orally immunized with S. typhi vaccine strains is significantly elevated in response to S. typhi flagella antigen in comparison with nonvaccinated controls [29]; iii) a murine ligated intestinal loop has been shown to secrete IL-6 following S. typhimurium exposure [76]. However, IL-6 secretion in vitro by intestinal epithelial cell lines in response to Salmonella spp. seems to vary according to the bacterial serotype [77, 78]. Nevertheless, expression of murine IL-6 in a recombinant S. typhimurium vaccine strain, despite its not affecting the humoral immune response, leads to reduced invasiveness in orally inoculated mice [79]. Since IL-10 antagonizes IFN-γ effects on macrophages and inhibits the host response mediated by macrophages, some experiments have been designed to question whether this cytokine may be involved in susceptibility to Salmonella infection. Although Eckmann et al. have not detected any difference in IL-10 mRNA induction between innately susceptible and resistant mouse strains following inoculation [38], Pie et al. have found enhanced IL-10 mRNA expression and IL-10 secretion in Nramp1s Microbes and Infection 1999, 719-726
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mice [39]. These differences may be attributed to the differences in Salmonella strains used (dublin and typhimurium, respectively), in the inoculation doses used (Pie et al. used the same dose for Nramp1r and Nramp1s mice, whereas Eckmann et al. used a lower dose for susceptible mice), and in the inoculation route (i.p. and i.v., respectively).
5. Assessment and future developments After describing the cytokine responses to Salmonella infection, it is quite difficult to picture a general mechanism of immune cell cross-talk via the cytokine array involved. However, the initial important roles of IL-12, IFN-γ, and TNF-α in triggering an efficient immune response can be outlined. IL-12 being the inducer of IFN-γ and IFN-γ being able to act in synergy with TNF-α, all participate together through the decisive function of the macrophage in innate immunity to salmonella and its interface with the development of acquired immunity. This is rather consistent with a type-1 orientation of the cytokine response. Interestingly, Nramp1s macrophages show deficiency in that they are unresponsive to exogenous IL-1 or GMCSF [70, 72]. In order to better understand the mechanism of early resistance to Salmonella infection under the genetic control of the Nramp1 gene, it seems valuable to examine at the molecular level the precise cytokinemediated events that may influence resistance or susceptibility to salmonella. A promising way to get insight into the molecular basis underlying the genetic difference between Nramp1r and Nramp1s individuals could be through the analysis of cell signalling events associated with cytokine response in macrophages. This approach is in agreement with the different hypotheses previously formulated for the function of the Nramp1 gene product (see [13] for review): sequence homology with the transmembrane carriage system including ion or nitrate transporter; proline content of the N-terminal region ressembling an SH3 domain that could interact with tyrosine kinases or cytoskeletal elements; and homology with yeast mitochondrial protein import. In this respect, recent work has brought new insights into the phenotypic differences between Nramp1r and Nramp1s macrophages related to protein kinase C deficiency, which could contribute to altered responsiveness to IFN-γ in Nramp1s macrophages [80]. Finally, it could be very informative to learn about the integrity of the JAK/STAT signalling pathways, specific for cytokine receptors, or about other important pathways involving protein kinase C and transcription factors such as NF-κB or PU1. For example, STAT1 deficiency has been shown to lead to marked unresponsiveness to IFN-α and -γ and increased susceptibility to microbial pathogens [81, 82]. These approaches could shed light on new ways for correcting the deficient phenotype in susceptible individuals and could emerge into new therapeutic applications. 723
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References [1] Meslin F.X., Global aspects of emerging and potential zoonoses: a WHO perspective, Emerg. Infect. Dis. 2 (1997) 223–228. [2] Kaufmann S.H.E., Immunity to intracellular bacteria,Ann. Rev. Immunol. 11 (1993) 129–163. [3] Liles W.C., VanVoorhis W.C., Review: nomenclature and biologic significance of cytokines involved in inflammation and the host immune response, J. Infect. Dis. 172 (1995) 1573–1580. [4] Lin R., Tarr P.E., Jones T.C., Present status of the use of cytokines as adjuvants with vaccines to protect against infectious dieases, Clin. Infect. Dis. 21 (1995) 1439–1449. [5] Mastroeni P., Harrison J.A., Hormaeche C.E., Natural resistance and acquired immunity to Salmonella, Fund. Clin. Immunol. 2 (1994) 83–95. [6] Jones B.D., Falkow S., Salmonellosis: host immune responses and bacterial virulence determinants, Annu. Rev. Immunol. 14 (1996) 533–561. [7] Berthon P., Bernard S., Lantier F., Immunohistochemical studies of sheep lymph nodes after subcutaneous inoculation of Salmonella abortusovis, Proceedings of the Fourth International Veterinary Immunology Symposium, University of California, Davis, in: Gershwin L., Lunney J., Schore C. (Eds.), 1995, pp. 269. [8] Gohin I., Olivier M., Lantier I., Pepin M., Lantier F., Analysis of the immune response in sheep efferent lymph during Salmonella abortusovis infection, Vet. Immunol. Immunopathol. 60 (1997) 111–130. [9] Mastroeni P., Villareal-Ramos B., Hormaeche C.E., Adoptive transfer of immunity to oral challenge with virulent Salmonellae in innately susceptible BALB/c mice requires both immune serum and T cells, Infect. Immun. 61 (1993) 3981–3984. [10] Lantier F., Pardon P., Marly J., Immunogenicity of a lowvirulence vaccinal strain against Salmonella abortus-ovis infection in mice, Infect. Immun. 40 (1983) 601–607. [11] Eisenstein T.K., Killar L.M., Sultzer B.M., Immunity to infection with Salmonella typhimurium: mouse strain differences in vaccine- and serum-mediated protection, J. Infect. Dis. 150 (1984) 425. [12] Malo D., Skamene E., Genetic control of host resistance to infection, Trends Genet. 10 (1994) 365–371. [13] Skamene E., Schurr E., Gros P., Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections, Annu. Rev. Med. 49 (1998) 275–287. [14] Govoni G., Gauthier S., Billia F., Iscove N.N., Gros P., Cell-specific and inducible Nramp1 gene expression in mouse macrophages in vitro and in vivo, J. Leukoc. Biol. 62 (1997) 277–286. [15] Bussmann V., Lantier I., Pitel F et al cDNA cloning structural organization and expression of the sheep NRAMP1 gene, Mamm. Gen. (1998) 1027–1031. [16] Hu J., Bumstead N., Skamene E., Gros P., Malo D., Structural organization, sequence and expression of the chicken NRAMP1 gene encoding the natural resistance-associated macrophage protein 1 DNA, Cell Biol. 15 (1996) 113–123. 724
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[17] Feng J., Li Y., Hashad M et al Bovine natural resistance associated macrophage protein 1 (Nramp1) gene, Genome Res. 6 (1996) 956–964. [18] Gruner L., Lantier F., Breeding for resistance to infectious diseases of small ruminants in Europe,Breeding for resistance to infectious dideases in small ruminants, Australian Center for International Agricultural Research Canberra, Australia, in: Gray G. D., Woolaston R.R., Eaton B.T. (Eds.), 1995, 99–117. [19] DeJong R., Altare F., Haagen I.A. et al Severe mycobacterial and Salmonella infections in interleukin-12 receptordeficient patients, Science 280 (1998) 1435–1438. [20] Henderson B., Poole S., Wilson M., Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis, Microbiol. Rev. 60 (1996) 316–341. [21] Wilson M., Seymour R., Henderson B., Bacterial perturbation of cytokine networks, Infect. Immun. 66 (1998) 2401–2409. [22] Ciacci-Woolwine F., Blomfield I.C., Richardson S.H., Mizel S.B., Salmonella flagellin induces tumour necrosis factor alpha in a human promonocytic cell line, Infect. Immun. 66 (1998) 1127–1134. [23] Mosmann T.R., Coffman R.L., Th1 and Th2 cells: different patterns of lymphokine secretions lead to different functionnal properties, Annu. Rev. Immunol. 7 (1989) 145–173. [24] Sher A., Coffman R.L., Regulation of immunity to parasites by T cells and T cell-derived cytokines, Annu. Rev. Immunol. 10 (1992) 385–409. [25] Soo S.S., Villareaol-Ramos B., AnjamKhan C.M., Hormaeche C.E., Blackwell J.M., Genetic control of immune response to recombinant antigens carried by an attenuated Salmonella typhimurium vaccine strain: Nramp1 influences T-helper subset responses and protection against leishmanial challenge, Infect. Immun. 66 (1998) 1910–1917. [26] Enomoto A., Nishimura H., Yoshikai Y., Predominant appearance of NK1.1+ T cells producing IL-4 may be involved in the increased susceptibility of mice with the beige mutation during Salmonella infection, J. Immunol. 158 (1997) 2268–2277. [27] Ramarathinam L., Shaban R.A., Niesel D.W., Klimpel G.R., IFN-γ production by gut-associated lymphoid tissue and spleen following oral S. typhimurium challenge, Microb. Pathogen. 11 (1991) 347–356. [28] Kumazawa Y., Freudenberg M., Hausmann C., MedingSlade S., Langhorne J., Galanos C., Formation of interferongamma and tumour necrosis factor in mice during Salmonella typhimurium infection, Pathobiology 59 (1991) 194–196. [29] Sztein M.B., Wasserman S.S., Tacket C.O., Edelman R., Hone D., Lindberg A.A., Levine M.M., Cytokine production patterns and lymphoproliferative responses in volunteers orally immunized with attenuated vaccine strains of Salmonella typhi, J. Infect. Dis. 170 (1994) 1508–1517. [30] Muotiala A., Mäkelä P.H., The role of IFN-γ in murine Salmonella typhimurium infection, Microb. Pathogen. 8 (1990) 135–141. Microbes and Infection 1999, 719-726
Cytokine response and salmonellosis
[31] Gould C.L., Sonnenfeld G., Effect of treatment with interferon-γ and concanavalin A on the course of infection of mice with Salmonella typhimurium strain LT-2, J. Interferon Res. 7 (1987) 255–260. [32] Edwards C.K. III, Ghiasuddin S.M., Yunger L.M., Lorence R.M., Arkins S., Dantzer R., Kelley K.W., In vivo administration of recombinant growth hormone or gamma interferon activates macrophages: enhanced resistance to experimental Salmonella typhimurium infection is correlated with generation of reactive oxygen intermediates, Infect. Immun. 60 (1992) 2514–2521. [33] Van Dissel J.T., Stikkelbroeck J.J.M., Michel B.C., Van Den Barselaar M.T., Leijh P.C.J., VanFurth R., Inability of recombinant interferon-γ to activate the antibacterial activity of mouse peritoneal macrophages against Listeria monocytogenes and Salmonella typhimurium, J. Immunol. 139 (1987) 1673–1678. [34] Kagaya K., Watanabe K., Fukazawa Y., Capacity of recombinant gamma interferon to activate macrophages for Salmonella-killing activity, Infect. Immun. 57 (1989) 609–615. [35] Nauciel C., Espinasse-Maes F., Role of gamma interferon and tumour necrosis factor alpha in resistance to Salmonella typhimurium infection, Infect. Immun. 60 (1992) 450–454. [36] Gulig P.A., Doyle T.J., Clare-Salzler M.J., Maiese R.L., Matsui H., Systemic infection of mice by wild-type but not spv- Salmonella typhimurium is enhanced by neutralization of gamma interferon and tumour necrosis factor alpha, Infect. Immun. 65 (1997) 5191–5197. [37] Hess J., Ladel C., Miko D., Kaufmann S.H.E., Salmonella typhimurium aroA- infection in gene-targeted immunodeficient mice, J. Immunol. 156 (1996) 3321–3326. [38] Eckmann L., Fierer J., Kagnoff M.F., Genetically resistant (Ityr) and susceptible (Itys) congenic mouse strains show similar cytokine responses following infection with Salmonella dublin, J. Immunol. 156 (1996) 2894–2900. [39] Pie S., Matsiota-Bernard P., Truffa-Bachi P., Nauciel C., Gamma interferon and interleukin-10 gene expression in innately susceptible and resistant mice during the early phase of Salmonella typhimurium infection, Infect. Immun. 64 (1996) 849–854. [40] Kita E., Emoto M., Oku D., Nishikawa F., Hamuro A., Kamikaidou N., Kashiba S., Contribution of interferon γ and membrane-associated interleukin 1 to the resistance to murine typhoid of Ityr mice, J. Leukoc. Biol. 51 (1992) 244–250. [41] Ramarathinam L., Niesel D.W., Klimpel G.R., Ity influences the production of IFN-γ by murine splenocytes stimulated in vitro with Salmonella typhimurium, J. Immunol. 150 (1993) 3965–3972. [42] Benbernou N., Nauciel C., Influence of mouse genotype and bacterial virulence in the generation of interferon-γproducing cells during the early phase of Salmonella typhimurium infection, Immunology 83 (1994) 245–249. [43] Jouanguy E., Lamhamedi-Cherradi S., Altare F et al Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis, J. Clin. Invest. 100 (1997) 2658–2664. Microbes and Infection 1999, 719-726
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[44] Mastroeni P., Clare S., Khan J.A et al Interleukin 18 contributes to host resistance and gamma interferon production in mice infected with virulent Salmonella typhimurium, Infect. Immun. 67 (1999) 478–483. [45] Chan S.H., Perussia B., Gupta J.W et al Induction of interferon-γ production by natural killer cell stimulatory factor: characterization of the responding cells and synergy with others inducers, J. Exp. Med. 173 (1991) 869–879. [46] Wolf S.F., Temple P.A., Kobayashi M. et al., Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells, J. Immunol. 146 (1991) 3074–3081. [47] Heinzel F.P., Rerko R.M., Ling P., Hakimi J., Shoenhaut D.S., Interleukin 12 is produced in vivo during endotoxemia and stimulates synthesis of gamma interferon, Infect. Immun. 62 (1994) 4244–4249. [48] Bost K.L., Clements J.D., In vivo induction of interleukin-12 mRNA expression after oral immunization with Salmonella dublin or the B subunit of Escherichia coli heat-labile enterotoxin, Infect. Immun. 63 (1995) 1076–1083. [49] Kincy-Cain T., Clements J.D., Bost K.L., Endogenous and Exogenous interleukin-12 augment the protective immune response in mice orally challenged with Salmonella dublin, Infect. Immun. 64 (1996) 1437–1440. [50] Mastroeni P., Harrison J.A., Chabalgoity J.A., Hormaeche C.E., Effect of interleukin 12 neutralization on host resistance and gamma interferon production in mouse typhoid, Infect. Immun. 64 (1996) 189–196. [51] Chong C., Bost K.L., Clements J.D., Differential production of interleukin-12 mRNA by murine macrophages in response to viable or killed Salmonella spp., Infect. Immun. 64 (1996) 1154–1160. [52] Bost K.L., Clements J.D., Intracellular Salmonella dublin induces substantial secretion of the 40-kilodalton subunit of interleukin-12 (IL-12) but minimal secretion of IL-12 as a 70-kilodalton protein in murine macrophages, Infect. Immun. 65 (1997) 3186–3192. [53] Mastroeni P., Harrison J.A., Robinson J.H. et al Interleukin-12 is required for control of the growth of attenuated aromatic-compound-dependent Salmonellae in BALB/c mice: role of gamma interferon and macrophage activation, Infect. Immun. 66 (1998) 4767–4776. [54] Cannon J.G., Tompkins R.G., Gelfland J.A et al Circulating interleukin 1 and tumor necrosis factor in septic shock and experimental fever, J. Infect. Dis. 161 (1990) 79–84. [55] Shibuya K., Robinson D., Zonin F et al IL-1α and TNF-α are required for IL-12-induced development of TH1 cells producing high levels of IFN-γ in BALB/c but not C57BL/6 mice, J. Immunol. 160 (1998) 1708–1716. [56] Peel J.E., Voirol M.J., Kolly C., Gobet D., Martinod S., Induction of circulating tumor necrosis factor cannot be demonstrated during septicemic salmonellosis in calves, Infect. Immun. 58 (1990) 439–442. [57] Jotwani R., Tanaka Y., Watanabe K., Tanaka K., Kato N., Ueno K., Cytokine stimulation during Salmonella typhimurium sepsis in Itys mice, J. Med. Microbiol. 42 (1995) 348–352. [58] Keuter M., Dharmana E., Gasem M.H et al Patterns of proinflammatory cytokines and inhibitors during typhoid fever, J. Infect. Dis. 169 (1994) 1306–1311. 725
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[59] Ciacci-Woolwine F., Kucera L.S., Richardson S.H., Iyer N.P., Mizel S.B., Salmonella activate tumor necrosis factor alpha production in a human promonocytic cell line via a released polypeptide, Infect. Immun. 65 (1997) 4624–4633. [60] Klimpel G.R., Shaban R., Niesel D.W., Bacteria-infected fibroblasts have enhanced susceptibility to the cytotoxic action of tumor necrosis factor, J. Immunol. 145 (1990) 711–717. [61] Nakano Y., Onozuka K., Terada Y., Shinomiya H., Nakano M., Protective effect of recombinant tumor necrosis factor-α in murine salmonellosis, J. Immunol. 144 (1990) 1935–1941. [62] Morrissey P.J., Charrier K., Vogel S.N., Exogenous tumor necrosis factor alpha and interleukin-1α increase resistance to Salmonella typhimurium: efficacy is influenced by the Ity and Lps loci, Infect. Immun. 63 (1995) 3196–3198. [63] Tite J.P., Dougan G., Chatfield S.N., The involvement of tumor necrosis factor in immunity to Salmonella infection, J. Immunol. 147 (1991) 3161–3164. [64] Mastroeni P., Arena A., Costa G.B., Liberto M.C., Bonina L., Hormaeche C.E., Serum TNFα in mouse typhoid and enhancement of a Salmonella infection by anti-TNFα antibodies, Microb. Pathogen. 11 (1991) 33–38. [65] Mastroeni P., Skepper J.N., Hormaeche C.E., Effect of anti-tumor necrosis factor alpha antibodies on histopathology of primary Salmonella infections, Infect. Immun. 63 (1995) 3674–3682. [66] Mastroeni P., Villareal-Ramos B., Hormaeche C.E., Role of T cells TNFα and IFNγ in recall of immunity to oral challenge with virulent Salmonellae in mice vaccinated with live attenuated aro- Salmonella vaccines, Microb. Pathogen. 13 (1992) 477–491. [67] Everest P., Roberts M., Dougan G., Susceptibility to Salmonella typhimurium infection and effectiveness of vaccination in mice deficient in the tumor necrosis factor alpha p55 receptor, Infect. Immun. 66 (1998) 3355–3364. [68] Mastroeni P., Villareal-Ramos B., Hormaeche C.E., Effect of late administration of anti-TNFα antibodies on a Salmonella infection in the mouse model, Microb. Pathogen. 14 (1993) 473–480. [69] Morrissey P.J., Charrier K., Interleukin-1 administration to C3H/HeJ mice after but not prior to infection increases resistance to Salmonella typhimurium, Infect. Immun. 59 (1991) 4729–4731. [70] Morrissey P.J., Charrier K., Treatment of mice with IL-1 before infection increases resistance to a lethal challenge with Salmonella typhimurium, J. Immunol. 153 (1994) 212–219. [71] Yamamoto Y., Klein T.W., Friedman H., Induction of cytokine granulocyte-macrophage colony-stimulating factor and chemokine macrophage inflammatory protein 2 mRNAs in macrophages by Legionella pneumophila or Salmonella typhimurium attachment requires different ligandreceptor systems, Infect. Immun. 64 (1996) 3062–3068.
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[72] Morrissey P.J., Charrier K., GM-CSF administration augments the survival of Ity-resistant A/J mice but not Itysusceptible C57BL/6 mice to a lethal challenge with Salmonella typhimurium, J. Immunol. 144 (1990) 557–561. [73] Denich K., Börlin P., O’Hanley P.D., Howard M., Heath A.W., Expression of the murine interleukin-4 gene in an attenuated aroA strain of Salmonella typhimurium: persistence and immune response in BALB/c mice and susceptibility to macrophage killing, Infect. Immun. 61 (1993) 4818–4827. [74] Everest P., Allen J., Papakonstantinopoulou A., Mastroeni P., Roberts M., Dougan G., Salmonella typhimurium infections in mice deficient in interleukin-4 production, J. Immunol. 159 (1997) 1820–1827. [75] Ramsay A.J., Husband A.J., Ramshaw I.A. et al The role of interleukin-6 in mucosal IgA antibody response in vivo, Science 264 (1994) 561–563. [76] Klimpel G.R., Asuncion M., Haithcoat J., Niesel D.W., Cholera toxin and Salmonella typhimurium induce different cytokine profiles in the gastrointestinal tract, Infect. Immun. 63 (1995) 1134–1137. [77] Weinstein D.L., O’Neill B.L., Metcalf E.S., Salmonella typhi stimulation of human intestinal epithelial cells induces secretion of epithelial cell-derived interleukin-6, Infect. Immun. 65 (1997) 395–404. [78] Weinstein D.L., O’Neill B.L., Hone D.M., Metcalf E.S., Differential early interactions between Salmonella enterica serovar typhi and two other pathogenic Salmonella serovars with intestinal epithelial cells, Infect. Immun. 66 (1998) 2310–2318. [79] Dunstan S.J., Ramsay A.J., Strugnell R.A., Studies of immunity and bacterial invasiveness in mice given a recombinant Salmonella vector encoding murine interleukin-6, Infect. Immun. 64 (1996) 2730–2736. [80] Olivier M., Cook P., Desanctis J., Hel Z., Wojciechowski W., Reiner N.E., Skamene E., Radzioch D., Phenotypic difference between Bcgr and Bcgs macrophages is related to differences in protein-kinase-C-dependent signalling, Eur. J. Biochem. 251 (1998) 734–743. [81] Durbin J.E., Hackenmiller R., Simon M.C., Levy D.E., Targeted disruption of the mouse STAT1 gene results in compromised innate immunity to viral disease, Cell 84 (1996) 443–450. [82] Meraz M.A., White J.M., Sheehan K.C.F. et al Targeted disruption of the STAT1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway, Cell 84 (1996) 431–442.
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Host cytokine response and resistance to Salmonella infection Anne-Christine Lalmanach*, Frédéric Lantier Institut national de la recherche agronomique, Centre de recherche de Tours, Laboratoire de pathologie infectieuse et immunologie, Nouzilly, France
ABSTRACT – Knowledge of the host response, of the resistance process, and of the mediators committed against Salmonella infection is essential to progress towards better means of prophylaxis and eradication. In this context, the present contribution attempts to interconnect, with the pivotal role of the macrophage, the early resistance process under the control of the Nramp1 gene and the cytokine response for resolving infection. IL-12 produced by macrophages is an inducer of IFN-γ production, which in turn activates the macrophage antibacterial activity and synergizes its effects with TNF-α. All three of these cytokines are powerful actors in the first line of anti-Salmonella defence. It can be pointed out that susceptible and resistant individuals do not seem to see the cytokine environment the same way, the former being unresponsive to IL-1 or GM-CSF treatment and deficient in IFN-γ production. These discrepancies may rely on cell signalling events that could be defective in macrophages of the susceptible phenotype. © Elsevier, Paris cytokines / disease-susceptibility – genetics / natural immunity / macrophages / Salmonella infections – animal
1. Introduction Invasive Salmonella species are causative agents of several gastrointestinal diseases and are responsible for enteric fevers in humans and several animal species. Salmonellae are still widespread enough to provoke typhoid fever or frequent cases of food poisoning, thus remaining a pathogen of interest in human health. Since Salmonella may be present in animals or products of animal origin, this bacterium represents a target pathogen for worldwide epidemiological surveillance and development of new means of eradication [1]. An undoubted way to control the spread of Salmonella is to reinforce the immune response of the host against this Gram-negative and facultative intracellular bacteria. Many cytokines possess the capacity to orchestrate immune cell migration, proliferation, activation, and interactions, which can culminate in antibacterial activity, and much information concerning the crucial role of the cytokines in host defence against infecting microorganisms is available (see [2] and [3] for review). Cytokines involved in resistance to infectious agents are of major importance when considering therapeutic plans and vaccine strategies. Some cytokines have already been used as adjuvants in vaccine design (see [4] for review) in order to boost the immune response. * Correspondence and reprints Microbes and Infection 1999, 719-726
The present review attempts to summarise recent data concerning the involvement of cytokines during the course of Salmonella infection. After presenting the elements of the immune response through the study of acquired and innate anti-Salmonella immunity, we will focus on the recent advances in research on cytokine response to Salmonella and its relationship with the resistance feature of the host.
2. Host immune response to Salmonella infection The immune response to primary Salmonella infection has been extensively studied (reviewed in [5] and [6]). The course of a sublethal challenge consists of i) rapid clearance of a large fraction of the inoculum; ii) early exponential growth of the remaining bacteria in the reticuloendothelial system (RES), mainly in mononuclear cells and in polymorphonuclear leucocytes; iii) suppression of the bacterial exponential growth in the RES, resulting in a plateau phase, in which macrophages and natural killer (NK) cells are the probable effector cells, with interferon (IFN)-γ and tumour necrosis factor (TNF)-α as mediators; and iv) clearance of the microorganisms from the tissues, which requires specific T-cell-dependent and major histocompatibility complex (MHC)-controlled immune mechanisms. 719
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In large animal species, such as sheep or cattle, it is possible to examine in detail the immune response induced in the lymph node draining the site of Salmonella inoculation by histological analysis or by a lymph cannulation technique, which allows a dynamic study of the immune response in vivo. It has thus been shown that both humoral and cellular responses are induced with the observation of a massive infiltration of polymorphonuclear leucocytes followed by lymphoid hyperplasia with prominent germinal centres [7]. The measure of the cell output in the efferent lymph reveals an important B lymphoblast export associated with an increase in antibody titres and an increase, 4 to 6 days postinoculation, in interleukin (IL)-1, TNF-α, IL-2, IFN-γ, and IL-4 mRNAs of efferent lymph cells [8]. The mechanism of long-term protection, which involves a specific recall of immunity (see [5] for review), is still highly disputed, probably because it depends on the host-parasite combinations, on the degree of Salmonella virulence, and on the innate resistance or susceptibility of the host. However, it has finally been shown that both humoral and cellular immunity is conferred by live vaccine immunization [9], which offers optimal protection in susceptible hosts [10]. Killed vaccines are only protective for innately resistant hosts, probably because they cannot induce cellular but only humoral responses [11].
3. Natural resistance to Salmonella infection: innate immunity Several mouse genes affecting resistance to primary invasive Salmonella infections have been more or less characterized (see [12] for review): among these are the genes Ity, for immunity to Salmonella typhimurium, Xid, for X-linked immunodeficiency, Nu, for nude gene, which is a pleiotropic mutation inducing a hairless phenotype and an impairment of T-cell development, and Lps, for response to bacterial lipopolysacharide. A role for MHCassociated genes and for as yet nonidentified ones on mouse chromosomes has also been reported. The survival of animals during the first phase of infection, before the development of specific acquired immunity, depends on their natural resistance, which controls the early exponential growth of Salmonellae in macrophages of the RES. This natural or innate resistance is under genetic control of the Nramp1 (for natural resistance-associated macrophage protein) gene of the Ity/Lsh/Bcg locus on chromosome 1, which regulates the growth of the intracellular pathogens S. typhimurium, Leishmania donovani, and Mycobacterium bovis, respectively (see [13] for review). A mutated allele of this gene determines the susceptibility to infection with several intracellular pathogens. In vitro, Nramp1 gene expression can be induced in mouse macrophage cell lines by IFN-γ and LPS treatment, which is equally efficient on macrophages in vivo after intraperitoneal injection [14]. Nramp1 has also been recently described in different species of domestic animals [15-17]. However, even if the structure of the Nramp1 gene product has been well characterized as a membrane protein closely related to the 720
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family of cation transporters, its precise function remains unknown, and its precise role in the mechanism underlying the resistant phenotype has not been elucidated so far. Although they have not yet been fully identified as genes of resistance to Salmonella infection, cytokine genes and cytokine receptor genes should also be considered as such. We have already predicted that in the near future a number of polymorphisms in cytokine genes will be identified, and that a number of them will be associated with susceptibility to infection, while genetic analysis of susceptibility to infection will increase in outbred populations, in humans, and domestic animals as well [18]. In fact, a mutation of the IL-12 receptor has recently been associated with severe susceptibility to Salmonella and to mycobacterial infections in humans [19].
4. Cytokines in response to Salmonella infection The severity and outcome of Salmonella infections are determined by multiple bacterial and host factors. Cytokines are key regulators of the host response to intracellular pathogens (see [3] for review). Various bacterial products from Salmonella are potent inducers of cytokine expression by immune cells [20-22]. Effector cells for Nramp1 genotype expression being macrophages, cytokines which can activate macrophages most likely contribute to the early resistance process. Furthermore, cytokines produced by macrophages and capable of triggering and/or enhancing an antibacterial immune response must be potent protagonists of the antiSalmonella defence (figure 1). Therefore, we will focus our analysis on the results concerning cytokines active on or produced by these cells and with known antiinfectious function. The role of IFN-γ, IL-12, TNF-α and IL-1 will thus be discussed in light of the recent literature, and the discussion will be extended to other cytokines, such as IL-4, GM-CSF, IL-6, and IL-10. The involvement of these cytokines in the resistant phenotype of infected individuals and consequently in the early resistance process will be analysed. This early cytokine response can probably condition the orientation of the subsequent T-cell response towards the type-1 or type-2 pattern of cytokine secretion described (see [23] and [24] for review). Essentially, the type-1 cytokine response is needed to resolve infection by various intracellular pathogens. This has been particularly well documented using experimental cutaneous Leishmania infection. However, the situation is not so clear-cut in the case of cytokine response to Salmonella. Very recent data demonstrate a predominant type-1 T-cell response (IL-2 and IFN-γ) to a recombinant Salmonella vaccine strain in mice carrying the Nramp1 gene resistant allele, associated with enhanced resolution of challenge infection with Leishmania, while Nramp1s mice mount a type-2 response (IL-4) and show exacerbated lesion growth upon challenge [25]. Another recent study has shown a disregulation of the type-1/type-2 balance in C57BL/6 mice with the beige mutation during Salmonella choleraesuis infection, manifested by an overproduction Microbes and Infection 1999, 719-726
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Figure 1. Cytokines, signals, and resistance to Salmonella infection: an overview of the early central role of the macrophage. Mononuclear phagocytes encountering bacteria or bacterial products such as lipopolysaccharide (LPS) can be triggered to react efficiently against the infectious process, especially if they harbour the resistant allele of the Nramp1 gene. This efficient reaction, beginning with phagocytosis, can be mediated by means of expression of various genes, such as cytokine genes (IL-1, IL-6, TNF-α or IL-12), involved in antigen presentation (MHC class II), or in bactericidal function (inducible nitric oxide synthase (iNOS)). The expression of such genes culminates in antiinfectious activity of the macrophage with the help of IFN-γ produced by NK cells and/or T cells and is connected with the acquired and cognate immune response mediated by T and B cells according to the helper T cell (TH) commitment type. Macrophage activation can be negatively regulated by IL-10 from type-2 TH cells (TH2).
of IL-4 associated with increased susceptibility compared with normal C57BL/6 mice, which produce mainly IFN-γ and are more resistant [26]. 4.1. IFN-γ
As a major candidate for enhancing macrophage antibacterial activity, IFN-γ has been extensively studied in salmonellosis, and IFN-γ involvement in resistance to Salmonella infection during the first week is well documented. IFN-γ is induced during the initial step of infection, since elevated levels of IFN-γ mRNA are found very early in the gut-associated lymphoid tissue and spleen of mice orally challenged with S. typhimurium [27]. Elevated levels of plasma IFN-γ have been recorded at day 3 postintraperitoneal infection with the same Salmonella serotype [28]. In vitro IFN-γ production by lymphocytes from human volunteers orally immunized with attenuated Salmonella typhi vaccines is also increased in response to antigen stimulation [29]. Systemic administration of this cytokine during the first few days after challenge with a virulent strain reduces the Microbes and Infection 1999, 719-726
severity of Salmonella infection in mice [30, 31] and rats [32]. Controversial results have shown the inability of recombinant IFN-γ (rIFN-γ) to activate in vitro or in vivo antibacterial activity of mouse peritoneal macrophages [33], while another study has demonstrated the enhanced Salmonella killing activity in rIFN-γ-activated macrophages in vitro [34]. The depletion of the cytokine by anti-IFN-γ treatment increases dramatically the severity of the disease [30], which is further amplified with concomitant treatment with anti-TNF-α antibody [35, 36]. Furthermore, mice unresponsive to IFN-γ (IFN-γR -/-) are highly susceptible to S. typhimurium aroA– infection [37]. Elsewhere, when comparing the responses of genetically resistant and susceptible mouse strains to Salmonella infection, the results are contradictory. Two studies have revealed no IFN-γmRNA production deficiency associated with susceptibility to Salmonella spp. [38, 39]. Others have suggested that early resistance of Nramp1r mice is partly attributable to their capacity to produce IFN-γ after infection [40], whereas susceptible (Nramp1s) mice fail to produce normal amounts of IFN-γ on the basis of in vitro 721
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experiments [41, 42]. Nevertheless, although it has not been reported in the case of salmonellosis, severe human mycobacterial infections can be associated with IFN-γ receptor gene deficiencies, which demonstrates the major role of this cytokine in resistance to intracellular pathogens [43]. The IFN-γ-producing cells during the first week of Salmonella infection are unlikely to be T lymphocytes, since depletion of these cells at this stage does not lead to major reduction of IFN-γ secretion [35]. Another study has reported the essential role of NK cells, and indirectly macrophages, in IFN-γ production by murine splenocytes after in vitro stimulation with S. typhimurium [41]. IL-18 is an inducer of IFN-γ production by NK cells and has recently been shown to mediate protection against Salmonella infection [44]. IL-12, a cytokine produced by macrophages, can also induce IFN-γ secretion by NK cells [45, 46]. These findings have thus prompted different groups to study the involvement of IL-12 in resistance to salmonellosis. 4.2. Il-12
The role of IL-12 as a proximal stimulator of IFN-γ release during endotoxemia has been reported [47]. Recent work has shown the important role of IL-12 in resistance to Salmonella infection. Following oral inoculation, Salmonella sp. induces IL-12 production at mucosal sites and in mesenteric lymph nodes [48, 49]. Furthermore, IL-12 neutralization with monoclonal antibodies reveals an IL-12-dependent mechanism of resistance in primary and secondary infections [49, 50]. Macrophages seem to be the cells responsible for IL-12 secretion upon vaccination with live Salmonella spp., and the protection efficiency is correlated with an increased production of IL-12 mRNA [51], although the major form secreted is the p40 subunit and not the complete bioactive 70-kDa form of IL-12 [52]. Elsewhere, the kinetics and magnitude of IL-12 mRNA expression in Nramp1s and Nramp1r mice following a Salmonella challenge are similar, thus demonstrating that IL-12 response is not essential in the expression of the resistant phenotype [38]. However, it has recently been reported that IL-12 receptor-deficient patients are highly susceptible and develop a severe Salmonella infection [19]. Finally, another recent work on a murine model of infection with an attenuated aroA Salmonella strain has shown that IL-12 neutralization induced a higher bacterial load in liver and spleen, associated with an infiltration of mononuclear cells instead of granuloma formation, and with reduced IFN-γ production, MHC class II antigen expression, and nitric oxide synthase activity. These impairments of host resistance means could be restored by administration of rIFN-γ to anti-IL-12-treated mice. These data are a major clue in the decisive interconnection between IL-12 and IFN-γ and their role in the restriction of Salmonella infection [53]. 4.3. IL-1 and TNF-α
The cytokines IL-1 and TNF-α are intimately associated in the mechanism of inflammation and the response to infectious agents. They have been implicated in the pathogenesis of sepsis caused by Gram-negative microorgan722
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isms [54]. These cytokines can synergize their activities and have been shown to be required for IL-12-induced development of type-1 T helper cells in BALB/c Nramp1s mice [55]. TNF-α production during salmonellosis remains controversial. Systemic TNF-α release in response to Salmonella infection has not been detected in mice [28] or even in the case of severe septicaemic salmonellosis in calves [56]. In these species, the TNF-α level seems to rise only in response to endotoxin or LPS injection. Nevertheless, an increase in the serum level of TNF-α has been measured after intraperitoneal challenge with S. typhimurium in mice [57] or in patients with typhoid fever [58]. In vitro, human promonocytic cell lines produce TNF-α in response to different Salmonella serotypes or in response to their released product [59]. TNF-α could play an important role in host defence against salmonellosis through its cytotoxic activity against Salmonella sp.-infected cells [60], although this cytotoxic effect was measured on fibroblasts, which are not the usual host target cells where salmonellae reside in vivo. Exogenous TNF-α can increase resistance to S. typhimurium infection [61], although data have shown that this increased survival after TNF-α treatment seems to be restricted to mice of the resistant phenotype [62]. Endogenous TNF-α production plays a role in the host response to the same Salmonella strain, since the administration of anti-TNF-α antibodies decreased resistance to infection [35, 63] by abolishing the plateau phase [64] and the concomitant and related granuloma formation in the RES [65]. TNF-α is also important in the specific recall of immunity to virulent salmonella conferred by immunization with live vaccines [66]. TNF-α receptor p55-deficient mice have been shown to succumb earlier to virulent S. typhimurium challenge and were not protected by an aroA– vaccine strain against the virulent strain [67]. TNF-α seems to be constantly required for the control of virulent salmonella in the RES, in both a sublethal primary infection in innately resistant mice and also in a secondary infection in innately susceptible mice immunized with a live vaccine [68]. IL-1 is also produced by macrophages in vitro, when primed by Salmonella infection in vivo [40]. Serum IL-1 level remains very low after S. typhimurium infection in mice, but these results have been obtained with Nramp1s mice only [57]. However, Salmonella dublin infection in both Nramp1r and Nramp1s mice is characterized by an increased expression of IL-1α mRNAs among other cytokines mRNAs [38]. IL-1 administration to mice increases the host resistance, although large variations in the response can be obtained according to the mouse strain studied: globally, IL-1 treatment is only beneficial prior to Salmonella infection in Nramp1r mice and after infection in Nramp1r Lpsd mice, but has no effect in Nramp1s mice [62, 69, 70]. Finally, TNF-α and IL-1 responses, which are associated with mouse survival in Salmonella infection, are not directly incriminated in the immune deficiency of mice of the Nramp1s phenotype, since the kinetics and magnitude of response of both cytokines are similar in innately susceptible and resistant mice [38]. Microbes and Infection 1999, 719-726
Cytokine response and salmonellosis
4.4. Other cytokines
Among the cytokines capable of eliciting macrophage activation and microbicidal activity, GM-CSF is a good candidate. During the initial step of infection, within a few hours, Salmonella attachment to macrophages in vitro increases production of GM-CSF as well as IL-1β and IL-6 mRNAs [71]. GM-CSF mRNA expression is also increased in vivo in spleen and liver within a few days following Salmonella infection but does not differ between susceptible and resistant mouse strains [38], although exogenous GM-CSF given during the course of a lethal Salmonella infection raises the survival of Nramp1r but not Nramp1s mice [72]. IL-4 is a mediator capable of directing helper T-cell precursor into a type-2 T helper cell differentiation in vitro and of changing orientation of the immune response towards type-2-induced humoral immunity (see [23] for review). IL-4 mRNA expression does not seem to be increased in response to virulent Salmonella infection in vivo [38]. However, if an IL-4 expression system is introduced into a live S. typhimurium vaccine vector, this generates higher growth and survival of Salmonella in BALB/c mice, with a noticeable alteration in macrophage killing activity in vitro [73]. Furthermore, increased killing and abcess development is observed in mice harbouring the wild-type IL-4 gene (IL-4 +/+) challenged with an S. typhimurium purE derivative than in mice harbouring the null allele (IL-4 -/-), even if both mouse groups exhibit a type-1 T-cell immune response [74]. Finally, multiple evidence tends to suggest that IL-4 has a deleterious effect on the host ability to protect against Salmonella spp. IL-6 was initially described as a B-cell terminal differentiation inducer. Besides being a component of the inflammatory response, IL-6 has been shown to play an important role in the mucosal antibody response in vivo [75]. Some evidence suggested a potent role for IL-6 in anti-Salmonella defence: i) patients suffering from typhoid fever present elevated IL-6 levels in the serum [58]; ii) IL-6 secretion by peripheral blood mononuclear cells of volunteers orally immunized with S. typhi vaccine strains is significantly elevated in response to S. typhi flagella antigen in comparison with nonvaccinated controls [29]; iii) a murine ligated intestinal loop has been shown to secrete IL-6 following S. typhimurium exposure [76]. However, IL-6 secretion in vitro by intestinal epithelial cell lines in response to Salmonella spp. seems to vary according to the bacterial serotype [77, 78]. Nevertheless, expression of murine IL-6 in a recombinant S. typhimurium vaccine strain, despite its not affecting the humoral immune response, leads to reduced invasiveness in orally inoculated mice [79]. Since IL-10 antagonizes IFN-γ effects on macrophages and inhibits the host response mediated by macrophages, some experiments have been designed to question whether this cytokine may be involved in susceptibility to Salmonella infection. Although Eckmann et al. have not detected any difference in IL-10 mRNA induction between innately susceptible and resistant mouse strains following inoculation [38], Pie et al. have found enhanced IL-10 mRNA expression and IL-10 secretion in Nramp1s Microbes and Infection 1999, 719-726
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mice [39]. These differences may be attributed to the differences in Salmonella strains used (dublin and typhimurium, respectively), in the inoculation doses used (Pie et al. used the same dose for Nramp1r and Nramp1s mice, whereas Eckmann et al. used a lower dose for susceptible mice), and in the inoculation route (i.p. and i.v., respectively).
5. Assessment and future developments After describing the cytokine responses to Salmonella infection, it is quite difficult to picture a general mechanism of immune cell cross-talk via the cytokine array involved. However, the initial important roles of IL-12, IFN-γ, and TNF-α in triggering an efficient immune response can be outlined. IL-12 being the inducer of IFN-γ and IFN-γ being able to act in synergy with TNF-α, all participate together through the decisive function of the macrophage in innate immunity to salmonella and its interface with the development of acquired immunity. This is rather consistent with a type-1 orientation of the cytokine response. Interestingly, Nramp1s macrophages show deficiency in that they are unresponsive to exogenous IL-1 or GMCSF [70, 72]. In order to better understand the mechanism of early resistance to Salmonella infection under the genetic control of the Nramp1 gene, it seems valuable to examine at the molecular level the precise cytokinemediated events that may influence resistance or susceptibility to salmonella. A promising way to get insight into the molecular basis underlying the genetic difference between Nramp1r and Nramp1s individuals could be through the analysis of cell signalling events associated with cytokine response in macrophages. This approach is in agreement with the different hypotheses previously formulated for the function of the Nramp1 gene product (see [13] for review): sequence homology with the transmembrane carriage system including ion or nitrate transporter; proline content of the N-terminal region ressembling an SH3 domain that could interact with tyrosine kinases or cytoskeletal elements; and homology with yeast mitochondrial protein import. In this respect, recent work has brought new insights into the phenotypic differences between Nramp1r and Nramp1s macrophages related to protein kinase C deficiency, which could contribute to altered responsiveness to IFN-γ in Nramp1s macrophages [80]. Finally, it could be very informative to learn about the integrity of the JAK/STAT signalling pathways, specific for cytokine receptors, or about other important pathways involving protein kinase C and transcription factors such as NF-κB or PU1. For example, STAT1 deficiency has been shown to lead to marked unresponsiveness to IFN-α and -γ and increased susceptibility to microbial pathogens [81, 82]. These approaches could shed light on new ways for correcting the deficient phenotype in susceptible individuals and could emerge into new therapeutic applications. 723
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References [1] Meslin F.X., Global aspects of emerging and potential zoonoses: a WHO perspective, Emerg. Infect. Dis. 2 (1997) 223–228. [2] Kaufmann S.H.E., Immunity to intracellular bacteria,Ann. Rev. Immunol. 11 (1993) 129–163. [3] Liles W.C., VanVoorhis W.C., Review: nomenclature and biologic significance of cytokines involved in inflammation and the host immune response, J. Infect. Dis. 172 (1995) 1573–1580. [4] Lin R., Tarr P.E., Jones T.C., Present status of the use of cytokines as adjuvants with vaccines to protect against infectious dieases, Clin. Infect. Dis. 21 (1995) 1439–1449. [5] Mastroeni P., Harrison J.A., Hormaeche C.E., Natural resistance and acquired immunity to Salmonella, Fund. Clin. Immunol. 2 (1994) 83–95. [6] Jones B.D., Falkow S., Salmonellosis: host immune responses and bacterial virulence determinants, Annu. Rev. Immunol. 14 (1996) 533–561. [7] Berthon P., Bernard S., Lantier F., Immunohistochemical studies of sheep lymph nodes after subcutaneous inoculation of Salmonella abortusovis, Proceedings of the Fourth International Veterinary Immunology Symposium, University of California, Davis, in: Gershwin L., Lunney J., Schore C. (Eds.), 1995, pp. 269. [8] Gohin I., Olivier M., Lantier I., Pepin M., Lantier F., Analysis of the immune response in sheep efferent lymph during Salmonella abortusovis infection, Vet. Immunol. Immunopathol. 60 (1997) 111–130. [9] Mastroeni P., Villareal-Ramos B., Hormaeche C.E., Adoptive transfer of immunity to oral challenge with virulent Salmonellae in innately susceptible BALB/c mice requires both immune serum and T cells, Infect. Immun. 61 (1993) 3981–3984. [10] Lantier F., Pardon P., Marly J., Immunogenicity of a lowvirulence vaccinal strain against Salmonella abortus-ovis infection in mice, Infect. Immun. 40 (1983) 601–607. [11] Eisenstein T.K., Killar L.M., Sultzer B.M., Immunity to infection with Salmonella typhimurium: mouse strain differences in vaccine- and serum-mediated protection, J. Infect. Dis. 150 (1984) 425. [12] Malo D., Skamene E., Genetic control of host resistance to infection, Trends Genet. 10 (1994) 365–371. [13] Skamene E., Schurr E., Gros P., Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections, Annu. Rev. Med. 49 (1998) 275–287. [14] Govoni G., Gauthier S., Billia F., Iscove N.N., Gros P., Cell-specific and inducible Nramp1 gene expression in mouse macrophages in vitro and in vivo, J. Leukoc. Biol. 62 (1997) 277–286. [15] Bussmann V., Lantier I., Pitel F et al cDNA cloning structural organization and expression of the sheep NRAMP1 gene, Mamm. Gen. (1998) 1027–1031. [16] Hu J., Bumstead N., Skamene E., Gros P., Malo D., Structural organization, sequence and expression of the chicken NRAMP1 gene encoding the natural resistance-associated macrophage protein 1 DNA, Cell Biol. 15 (1996) 113–123. 724
Lalmanach and Lantier
[17] Feng J., Li Y., Hashad M et al Bovine natural resistance associated macrophage protein 1 (Nramp1) gene, Genome Res. 6 (1996) 956–964. [18] Gruner L., Lantier F., Breeding for resistance to infectious diseases of small ruminants in Europe,Breeding for resistance to infectious dideases in small ruminants, Australian Center for International Agricultural Research Canberra, Australia, in: Gray G. D., Woolaston R.R., Eaton B.T. (Eds.), 1995, 99–117. [19] DeJong R., Altare F., Haagen I.A. et al Severe mycobacterial and Salmonella infections in interleukin-12 receptordeficient patients, Science 280 (1998) 1435–1438. [20] Henderson B., Poole S., Wilson M., Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis, Microbiol. Rev. 60 (1996) 316–341. [21] Wilson M., Seymour R., Henderson B., Bacterial perturbation of cytokine networks, Infect. Immun. 66 (1998) 2401–2409. [22] Ciacci-Woolwine F., Blomfield I.C., Richardson S.H., Mizel S.B., Salmonella flagellin induces tumour necrosis factor alpha in a human promonocytic cell line, Infect. Immun. 66 (1998) 1127–1134. [23] Mosmann T.R., Coffman R.L., Th1 and Th2 cells: different patterns of lymphokine secretions lead to different functionnal properties, Annu. Rev. Immunol. 7 (1989) 145–173. [24] Sher A., Coffman R.L., Regulation of immunity to parasites by T cells and T cell-derived cytokines, Annu. Rev. Immunol. 10 (1992) 385–409. [25] Soo S.S., Villareaol-Ramos B., AnjamKhan C.M., Hormaeche C.E., Blackwell J.M., Genetic control of immune response to recombinant antigens carried by an attenuated Salmonella typhimurium vaccine strain: Nramp1 influences T-helper subset responses and protection against leishmanial challenge, Infect. Immun. 66 (1998) 1910–1917. [26] Enomoto A., Nishimura H., Yoshikai Y., Predominant appearance of NK1.1+ T cells producing IL-4 may be involved in the increased susceptibility of mice with the beige mutation during Salmonella infection, J. Immunol. 158 (1997) 2268–2277. [27] Ramarathinam L., Shaban R.A., Niesel D.W., Klimpel G.R., IFN-γ production by gut-associated lymphoid tissue and spleen following oral S. typhimurium challenge, Microb. Pathogen. 11 (1991) 347–356. [28] Kumazawa Y., Freudenberg M., Hausmann C., MedingSlade S., Langhorne J., Galanos C., Formation of interferongamma and tumour necrosis factor in mice during Salmonella typhimurium infection, Pathobiology 59 (1991) 194–196. [29] Sztein M.B., Wasserman S.S., Tacket C.O., Edelman R., Hone D., Lindberg A.A., Levine M.M., Cytokine production patterns and lymphoproliferative responses in volunteers orally immunized with attenuated vaccine strains of Salmonella typhi, J. Infect. Dis. 170 (1994) 1508–1517. [30] Muotiala A., Mäkelä P.H., The role of IFN-γ in murine Salmonella typhimurium infection, Microb. Pathogen. 8 (1990) 135–141. Microbes and Infection 1999, 719-726
Cytokine response and salmonellosis
[31] Gould C.L., Sonnenfeld G., Effect of treatment with interferon-γ and concanavalin A on the course of infection of mice with Salmonella typhimurium strain LT-2, J. Interferon Res. 7 (1987) 255–260. [32] Edwards C.K. III, Ghiasuddin S.M., Yunger L.M., Lorence R.M., Arkins S., Dantzer R., Kelley K.W., In vivo administration of recombinant growth hormone or gamma interferon activates macrophages: enhanced resistance to experimental Salmonella typhimurium infection is correlated with generation of reactive oxygen intermediates, Infect. Immun. 60 (1992) 2514–2521. [33] Van Dissel J.T., Stikkelbroeck J.J.M., Michel B.C., Van Den Barselaar M.T., Leijh P.C.J., VanFurth R., Inability of recombinant interferon-γ to activate the antibacterial activity of mouse peritoneal macrophages against Listeria monocytogenes and Salmonella typhimurium, J. Immunol. 139 (1987) 1673–1678. [34] Kagaya K., Watanabe K., Fukazawa Y., Capacity of recombinant gamma interferon to activate macrophages for Salmonella-killing activity, Infect. Immun. 57 (1989) 609–615. [35] Nauciel C., Espinasse-Maes F., Role of gamma interferon and tumour necrosis factor alpha in resistance to Salmonella typhimurium infection, Infect. Immun. 60 (1992) 450–454. [36] Gulig P.A., Doyle T.J., Clare-Salzler M.J., Maiese R.L., Matsui H., Systemic infection of mice by wild-type but not spv- Salmonella typhimurium is enhanced by neutralization of gamma interferon and tumour necrosis factor alpha, Infect. Immun. 65 (1997) 5191–5197. [37] Hess J., Ladel C., Miko D., Kaufmann S.H.E., Salmonella typhimurium aroA- infection in gene-targeted immunodeficient mice, J. Immunol. 156 (1996) 3321–3326. [38] Eckmann L., Fierer J., Kagnoff M.F., Genetically resistant (Ityr) and susceptible (Itys) congenic mouse strains show similar cytokine responses following infection with Salmonella dublin, J. Immunol. 156 (1996) 2894–2900. [39] Pie S., Matsiota-Bernard P., Truffa-Bachi P., Nauciel C., Gamma interferon and interleukin-10 gene expression in innately susceptible and resistant mice during the early phase of Salmonella typhimurium infection, Infect. Immun. 64 (1996) 849–854. [40] Kita E., Emoto M., Oku D., Nishikawa F., Hamuro A., Kamikaidou N., Kashiba S., Contribution of interferon γ and membrane-associated interleukin 1 to the resistance to murine typhoid of Ityr mice, J. Leukoc. Biol. 51 (1992) 244–250. [41] Ramarathinam L., Niesel D.W., Klimpel G.R., Ity influences the production of IFN-γ by murine splenocytes stimulated in vitro with Salmonella typhimurium, J. Immunol. 150 (1993) 3965–3972. [42] Benbernou N., Nauciel C., Influence of mouse genotype and bacterial virulence in the generation of interferon-γproducing cells during the early phase of Salmonella typhimurium infection, Immunology 83 (1994) 245–249. [43] Jouanguy E., Lamhamedi-Cherradi S., Altare F et al Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis, J. Clin. Invest. 100 (1997) 2658–2664. Microbes and Infection 1999, 719-726
Review
[44] Mastroeni P., Clare S., Khan J.A et al Interleukin 18 contributes to host resistance and gamma interferon production in mice infected with virulent Salmonella typhimurium, Infect. Immun. 67 (1999) 478–483. [45] Chan S.H., Perussia B., Gupta J.W et al Induction of interferon-γ production by natural killer cell stimulatory factor: characterization of the responding cells and synergy with others inducers, J. Exp. Med. 173 (1991) 869–879. [46] Wolf S.F., Temple P.A., Kobayashi M. et al., Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells, J. Immunol. 146 (1991) 3074–3081. [47] Heinzel F.P., Rerko R.M., Ling P., Hakimi J., Shoenhaut D.S., Interleukin 12 is produced in vivo during endotoxemia and stimulates synthesis of gamma interferon, Infect. Immun. 62 (1994) 4244–4249. [48] Bost K.L., Clements J.D., In vivo induction of interleukin-12 mRNA expression after oral immunization with Salmonella dublin or the B subunit of Escherichia coli heat-labile enterotoxin, Infect. Immun. 63 (1995) 1076–1083. [49] Kincy-Cain T., Clements J.D., Bost K.L., Endogenous and Exogenous interleukin-12 augment the protective immune response in mice orally challenged with Salmonella dublin, Infect. Immun. 64 (1996) 1437–1440. [50] Mastroeni P., Harrison J.A., Chabalgoity J.A., Hormaeche C.E., Effect of interleukin 12 neutralization on host resistance and gamma interferon production in mouse typhoid, Infect. Immun. 64 (1996) 189–196. [51] Chong C., Bost K.L., Clements J.D., Differential production of interleukin-12 mRNA by murine macrophages in response to viable or killed Salmonella spp., Infect. Immun. 64 (1996) 1154–1160. [52] Bost K.L., Clements J.D., Intracellular Salmonella dublin induces substantial secretion of the 40-kilodalton subunit of interleukin-12 (IL-12) but minimal secretion of IL-12 as a 70-kilodalton protein in murine macrophages, Infect. Immun. 65 (1997) 3186–3192. [53] Mastroeni P., Harrison J.A., Robinson J.H. et al Interleukin-12 is required for control of the growth of attenuated aromatic-compound-dependent Salmonellae in BALB/c mice: role of gamma interferon and macrophage activation, Infect. Immun. 66 (1998) 4767–4776. [54] Cannon J.G., Tompkins R.G., Gelfland J.A et al Circulating interleukin 1 and tumor necrosis factor in septic shock and experimental fever, J. Infect. Dis. 161 (1990) 79–84. [55] Shibuya K., Robinson D., Zonin F et al IL-1α and TNF-α are required for IL-12-induced development of TH1 cells producing high levels of IFN-γ in BALB/c but not C57BL/6 mice, J. Immunol. 160 (1998) 1708–1716. [56] Peel J.E., Voirol M.J., Kolly C., Gobet D., Martinod S., Induction of circulating tumor necrosis factor cannot be demonstrated during septicemic salmonellosis in calves, Infect. Immun. 58 (1990) 439–442. [57] Jotwani R., Tanaka Y., Watanabe K., Tanaka K., Kato N., Ueno K., Cytokine stimulation during Salmonella typhimurium sepsis in Itys mice, J. Med. Microbiol. 42 (1995) 348–352. [58] Keuter M., Dharmana E., Gasem M.H et al Patterns of proinflammatory cytokines and inhibitors during typhoid fever, J. Infect. Dis. 169 (1994) 1306–1311. 725
Review
[59] Ciacci-Woolwine F., Kucera L.S., Richardson S.H., Iyer N.P., Mizel S.B., Salmonella activate tumor necrosis factor alpha production in a human promonocytic cell line via a released polypeptide, Infect. Immun. 65 (1997) 4624–4633. [60] Klimpel G.R., Shaban R., Niesel D.W., Bacteria-infected fibroblasts have enhanced susceptibility to the cytotoxic action of tumor necrosis factor, J. Immunol. 145 (1990) 711–717. [61] Nakano Y., Onozuka K., Terada Y., Shinomiya H., Nakano M., Protective effect of recombinant tumor necrosis factor-α in murine salmonellosis, J. Immunol. 144 (1990) 1935–1941. [62] Morrissey P.J., Charrier K., Vogel S.N., Exogenous tumor necrosis factor alpha and interleukin-1α increase resistance to Salmonella typhimurium: efficacy is influenced by the Ity and Lps loci, Infect. Immun. 63 (1995) 3196–3198. [63] Tite J.P., Dougan G., Chatfield S.N., The involvement of tumor necrosis factor in immunity to Salmonella infection, J. Immunol. 147 (1991) 3161–3164. [64] Mastroeni P., Arena A., Costa G.B., Liberto M.C., Bonina L., Hormaeche C.E., Serum TNFα in mouse typhoid and enhancement of a Salmonella infection by anti-TNFα antibodies, Microb. Pathogen. 11 (1991) 33–38. [65] Mastroeni P., Skepper J.N., Hormaeche C.E., Effect of anti-tumor necrosis factor alpha antibodies on histopathology of primary Salmonella infections, Infect. Immun. 63 (1995) 3674–3682. [66] Mastroeni P., Villareal-Ramos B., Hormaeche C.E., Role of T cells TNFα and IFNγ in recall of immunity to oral challenge with virulent Salmonellae in mice vaccinated with live attenuated aro- Salmonella vaccines, Microb. Pathogen. 13 (1992) 477–491. [67] Everest P., Roberts M., Dougan G., Susceptibility to Salmonella typhimurium infection and effectiveness of vaccination in mice deficient in the tumor necrosis factor alpha p55 receptor, Infect. Immun. 66 (1998) 3355–3364. [68] Mastroeni P., Villareal-Ramos B., Hormaeche C.E., Effect of late administration of anti-TNFα antibodies on a Salmonella infection in the mouse model, Microb. Pathogen. 14 (1993) 473–480. [69] Morrissey P.J., Charrier K., Interleukin-1 administration to C3H/HeJ mice after but not prior to infection increases resistance to Salmonella typhimurium, Infect. Immun. 59 (1991) 4729–4731. [70] Morrissey P.J., Charrier K., Treatment of mice with IL-1 before infection increases resistance to a lethal challenge with Salmonella typhimurium, J. Immunol. 153 (1994) 212–219. [71] Yamamoto Y., Klein T.W., Friedman H., Induction of cytokine granulocyte-macrophage colony-stimulating factor and chemokine macrophage inflammatory protein 2 mRNAs in macrophages by Legionella pneumophila or Salmonella typhimurium attachment requires different ligandreceptor systems, Infect. Immun. 64 (1996) 3062–3068.
726
Lalmanach and Lantier
[72] Morrissey P.J., Charrier K., GM-CSF administration augments the survival of Ity-resistant A/J mice but not Itysusceptible C57BL/6 mice to a lethal challenge with Salmonella typhimurium, J. Immunol. 144 (1990) 557–561. [73] Denich K., Börlin P., O’Hanley P.D., Howard M., Heath A.W., Expression of the murine interleukin-4 gene in an attenuated aroA strain of Salmonella typhimurium: persistence and immune response in BALB/c mice and susceptibility to macrophage killing, Infect. Immun. 61 (1993) 4818–4827. [74] Everest P., Allen J., Papakonstantinopoulou A., Mastroeni P., Roberts M., Dougan G., Salmonella typhimurium infections in mice deficient in interleukin-4 production, J. Immunol. 159 (1997) 1820–1827. [75] Ramsay A.J., Husband A.J., Ramshaw I.A. et al The role of interleukin-6 in mucosal IgA antibody response in vivo, Science 264 (1994) 561–563. [76] Klimpel G.R., Asuncion M., Haithcoat J., Niesel D.W., Cholera toxin and Salmonella typhimurium induce different cytokine profiles in the gastrointestinal tract, Infect. Immun. 63 (1995) 1134–1137. [77] Weinstein D.L., O’Neill B.L., Metcalf E.S., Salmonella typhi stimulation of human intestinal epithelial cells induces secretion of epithelial cell-derived interleukin-6, Infect. Immun. 65 (1997) 395–404. [78] Weinstein D.L., O’Neill B.L., Hone D.M., Metcalf E.S., Differential early interactions between Salmonella enterica serovar typhi and two other pathogenic Salmonella serovars with intestinal epithelial cells, Infect. Immun. 66 (1998) 2310–2318. [79] Dunstan S.J., Ramsay A.J., Strugnell R.A., Studies of immunity and bacterial invasiveness in mice given a recombinant Salmonella vector encoding murine interleukin-6, Infect. Immun. 64 (1996) 2730–2736. [80] Olivier M., Cook P., Desanctis J., Hel Z., Wojciechowski W., Reiner N.E., Skamene E., Radzioch D., Phenotypic difference between Bcgr and Bcgs macrophages is related to differences in protein-kinase-C-dependent signalling, Eur. J. Biochem. 251 (1998) 734–743. [81] Durbin J.E., Hackenmiller R., Simon M.C., Levy D.E., Targeted disruption of the mouse STAT1 gene results in compromised innate immunity to viral disease, Cell 84 (1996) 443–450. [82] Meraz M.A., White J.M., Sheehan K.C.F. et al Targeted disruption of the STAT1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway, Cell 84 (1996) 431–442.
Microbes and Infection 1999, 719-726