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New insight into the role of dendritic cells in malaria immune pathogenesis
Update 6 Mitchell, S.E. and Read, A.F. (2005) Poor maternal environment enhances offspring disease resistance in an invertebrate. Proc. Biol. Sci. 272, 2601–2607 7 Sadd, B.M. and Schmid-Hempel, P. (2007) Facultative but persistent trans-generational immunity via the mother’s eggs in bumblebees. Curr. Biol. 17, R1046–R1047 8 Mech, L.D. et al. (1991) Effects of maternal and grandmaternal nutrition on deer mass and vulnerability to wolf predation. J. Mammal. 72, 146–151 9 Plaistow, S.J. et al. (2006) Context-dependent intergenerational effects: the interaction between past and present environments and its effect on population dynamics. Am. Nat. 167, 206–215 10 Ra¨sa¨nen, K. and Kruuk, L.E.B. (2007) Maternal effects and evolution at ecological time scales. Funct. Ecol. 21, 408–421 11 Benton, T.G. et al. (2005) Changes in maternal investment in eggs can affect population dynamics. Proc. Biol. Sci. 272, 1351–1356 12 Grech, K. et al. (2007) The effect of parental rearing conditions on offspring life-history in Anopheles stephensi. Malar. J. 6, 130 13 Minchella, D.J. (1985) Host life-history variation in response to parasitism. Parasitol. Today 9, 8–13 14 Hochberg, M.E.Y. et al. (1992) Parasitism as a constraint on the rate of life-history evolution. J. Evol. Biol. 5, 491–504 15 Forbes, M.R.L. (1993) Parasitism and host reproductive effort. Oikos 76, 444–450 16 Sorci, G. and Clobert, J. (1995) Effects of maternal parasite load on offspring life-history traits in the common lizard (Lacerta vivipara). J. Evol. Biol. 8, 711–723
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17 Grindstaff, J.L. et al. (2006) Trans-generational priming of immunity: maternal exposure to a bacterial antigen enhances offspring humoral immunity. Proc. Biol. Sci. 273, 2551–2557 18 Moret, Y. (2006) Trans-generational immune priming: specific enhancement of the antimicrobial immune response in the mealworm beetle, Tenebrio molitor. Proc. Biol. Sci. 273, 1399–1405 19 Little, T.J. et al. (2003) Maternal transfer of strain-specific immunity in an invertebrate. Curr. Biol. 13, 489–492 20 Koella, J.C. (1998) The malaria parasite, Plasmodium falciparum, increases the frequency of multiple feeding of its mosquito vector, Anopheles gambiae. Proc. Biol. Sci. 265, 763–768 21 Scholte, E-J. (2006) Infection of the malaria mosquito Anopheles gambiae with the entomopathogenic fungus Metarhizium anisopliae reduces blood feeding and fecundity. J. Invertebr. Pathol. 91, 43–49 22 Bull, J.J. (1994) Virulence. Evolution Int. J. Org. Evolution 48, 1423– 1437 23 Gu, W. and Nowak, R.J. (2005) Habitat-based modeling of impacts of mosquito larval interventions on entomological inoculation rates, incidence, and prevalence of malaria. Am. J. Trop. Med. Hyg. 73, 546–552 24 Killeen, G.F. (2002) Eradication of Anopheles gambiae from Brazil: lessons for malaria control in Africa? Lancet Infect. Dis. 2, 618–627 25 Phillips, R.S. (2001) Current status of malaria and potential for control. Clin. Microbiol. Rev. 14, 208–226 1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2008.02.004 Available online 9 April 2008
Research Focus
New insight into the role of dendritic cells in malaria immune pathogenesis Stephanie Bousheri and Huyen Cao California Department of Public Health, 850 Marina Bay Parkway, Richmond, CA 94804, USA
The mechanism by which the host develops protective immunity to malaria remains poorly understood. Dendritic cells (DCs) are central to the initiation and regulation of the adaptive immune response. Modulation of DC function might enable Plasmodium to evade the immune system. Millington et al. propose one mechanism by which malaria inhibits DC–T-cell interactions without interfering directly with T-cell receptor engagement. The consequence is a decrease in the co-stimulation required to develop an effective immune response.
leads to an effective immune control of the parasite, but their excessive production will result in severe clinical disease or death [1]. Malaria infection can also suppress the generation of antimalarial immune responses [2–4]. The suppression is thought to be mediated through apoptosis, parasite inhibition of macrophage activation and antigen processing and, more recently, through their inhibition of dendritic cell (DC) maturation or alteration of DC function [5,6]. These inhibitory mechanisms probably include the activation of the presenting DC.
Immunity to malaria infection is elusive Malaria is a devastating disease caused by the Plasmodium parasite, which kills nearly 3 million people and infects more than 400 million each year. Knowledge of the mechanisms leading to protective immunity is surprisingly limited. The optimal immune response to malaria infection involves early proinflammatory, cytokine-mediated, effector mechanisms that clear parasite-infected cells, which are then suppressed equally rapidly by anti-inflammatory effectors once parasite replication has been brought under control [1]. The immune mechanisms that control and kill the parasite are also implicated in subsequent immunopathology. Thus, a potent and timely response of inflammatory cytokines
DCs mediate the adaptive immune response DCs initiate the immune response by providing antigenic stimulation for T and B cells. DCs provide a crucial link between the innate and adaptive immune response and are specialized in the uptake, processing and presentation of antigens to T cells. These antigens are presented in the context of major histocompatibility complex (MHC) class II to T cells along with CD80/CD86 co-stimulations. DCs are the only antigen-presenting cells (APCs) that can activate naı¨ve T cells [7]. The activated T cells are then able to produce cytokines that promote the maturation of the cellular responses directly and help B cells produce antibody. These interactions initiate a cascade of cellular and molecular events that lead to an effective adaptive immune response. The precise nature of the DC–parasite inter-
Corresponding author: Otti, O. ([email protected]).
199
Update action in malaria thus has important consequences for both immunopathology and immunity. Malaria modulates the activation and function of DCs directly (reviewed in Ref. [8]), although controversies remain regarding the effect of infection on the biology of DCs. To function effectively as APCs, DCs undergo a process of maturation, characterized by increased expression of co-stimulatory markers, MHC and adhesion molecules, as well as the secretion of proinflammatory cytokines (reviewed in Ref. [9]). Activation and maturation of DCs during Plasmodium infection has been reported [10–16]. Infected red-blood cells (iRBCs) activate human plasmacytoid DCs [17], possibly through the action of hemozoin (HZ) [18], a by-product of a malaria infection, which appears to target Plasmodium falciparum DNA to intracellular Toll-like receptor 9 receptors [19]. Others, including Millington et al., have demonstrated that DC functions are impaired and suppression might be mediated by HZ [20,21]. HZ has been associated with decreased expression of MHC class II molecules as well as other co-stimulatory molecules, such as CD80 and CD40 [20,22], and inhibition of monocytes [20,22]. The apparent Plasmodium-induced DC suppression in some studies and activation in others might clearly reflect differences in the Plasmodium species studied, distinct DC subsets, or experimental methodologies (reviewed in Refs [15,23]). Millington et al. described findings whereby HZ-loaded DCs were unable to form stable interactions with T cells, failed to induce upregulation of CD40 and reduced the subsequent responsiveness to lipopolysaccharide stimulation [24]. The video accompanying the Millington et al. study of the multi-photon laser-scanning microscopy findings are visually striking. Images of fluorescent-labeled DCs and T cells were acquired sequentially to define the proportion of DCs in contact with T cells in the presence or absence of HZ or Plasmodium-infected RBCs. HZ-treated DCs accumulate the pigments rapidly and fail to form stable clusters with T cells; this results in decreased proliferation. Decreased T-cell motility and cluster formation was evident in the presence of in vitro HZ or in vivo P. chaubaudi. This impaired interaction does not appear to involve the processing and presentation of the antigen in the MHC–T-cell receptor context. Instead, the immediate cellular interaction is altered, such that stable clusters do not form, leading to an abnormal T-cell response. Implications of DC interactions with T cells A conclusive effect of malaria on the biology of DCs is difficult to ascertain, perhaps because of the complexity of the parasite and the DC system. The controversy as to whether DC function is altered uniformly by the malaria parasite might also relate to the abundance of different species of human and rodent Plasmodium and the distinct research approach and methodologies. Demonstration of whether the decreased clustering described by Millington et al. is the normal spectrum of inflammatory and immune response or whether the malaria parasite has evolved specific strategies to actively circumvent an appropriate T-cell response is necessary to further elucidate this interaction. Nevertheless, new insight into the mechanism of suppression has now been provided as one means by which 200
Trends in Parasitology Vol.24 No.5
P. falciparum–DC interactions might influence subsequent antimalarial immunity. References 1 Artavanis-Tsakonas, K. et al. (2003) The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology. Clin. Exp. Immunol. 133, 145–152 2 Riley, E.M. et al. (1989) CD8+ T cells inhibit Plasmodium falciparuminduced lymphoproliferation and gamma interferon production in cell preparations from some malaria-immune individuals. Infect. Immun. 57, 1281–1284 3 Wipasa, J. et al. (2001) Apoptotic deletion of Th cells specific for the 19kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection. J. Immunol. 167, 3903–3909 4 Luty, A.J. et al. (2000) Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect. Immun. 68, 3909–3915 5 Urban, B.C. et al. (1999) Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400, 73–77 6 Urban, B.C. and Roberts, D.J. (2003) Inhibition of T cell function during malaria: implications for immunology and vaccinology. J. Exp. Med. 197, 137–141 7 Banchereau, J. and Steinman, R.M. (1998) Dendritic cells and the control of immunity. Nature 392, 245–252 8 Wykes, M. et al. (2007) Dendritic cell biology during malaria. Cell. Microbiol. 9, 300–305 9 Reis e Sousa, C. (2006) Dendritic cells in a mature age. Nat. Rev. Immunol. 6, 476–483 10 Leisewitz, A.L. et al. (2004) Response of the splenic dendritic cell population to malaria infection. Infect. Immun. 72, 4233–4239 11 Coban, C. et al. (2002) Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine. Infect. Immun. 70, 3939–3943 12 Newman, K.C. et al. (2006) Cross-talk with myeloid accessory cells regulates human natural killer cell interferon-gamma responses to malaria. PLoS Pathog. 2, e118 13 Ing, R. et al. (2006) Interaction of mouse dendritic cells and malariainfected erythrocytes: uptake, maturation, and antigen presentation. J. Immunol. 176, 441–450 14 Perry, J.A. et al. (2004) Dendritic cells from malaria-infected mice are fully functional APC. J. Immunol. 172, 475–482 15 Sponaas, A.M. et al. (2006) Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-specific T cells. J. Exp. Med. 203, 1427–1433 16 Wilson, N.S. et al. (2006) Systemic activation of dendritic cells by Tolllike receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat. Immunol. 7, 165–172 17 Pichyangkul, S. et al. (2004) Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J. Immunol. 172, 4926–4933 18 Coban, C. et al. (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. 201, 19–25 19 Parroche, P. et al. (2007) Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc. Natl. Acad. Sci. U. S. A. 104, 1919–1924 20 Skorokhod, O.A. et al. (2004) Hemozoin (malarial pigment) inhibits differentiation and maturation of human monocyte-derived dendritic cells: a peroxisome proliferator-activated receptor-gamma-mediated effect. J. Immunol. 173, 4066–4074 21 Millington, O.R. et al. (2006) Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. J. Biol. 5, 5 22 Skorokhod, O. et al. (2005) Role of 4-hydroxynonenal in the hemozoinmediated inhibition of differentiation of human monocytes to dendritic cells induced by GM-CSF/IL-4. Biofactors 24, 283–289 23 Langhorne, J. et al. (2004) Dendritic cells, pro-inflammatory responses, and antigen presentation in a rodent malaria infection. Immunol. Rev. 201, 35–47 24 Millington, O.R. et al. (2007) Malaria impairs T cell clustering and immune priming despite normal signal 1 from dendritic cells. PLoS Pathog. 3, 1380–1387 1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2008.02.003 Available online 9 April 2008
Trends in Parasitology
Vol.24 No.5
17 Grindstaff, J.L. et al. (2006) Trans-generational priming of immunity: maternal exposure to a bacterial antigen enhances offspring humoral immunity. Proc. Biol. Sci. 273, 2551–2557 18 Moret, Y. (2006) Trans-generational immune priming: specific enhancement of the antimicrobial immune response in the mealworm beetle, Tenebrio molitor. Proc. Biol. Sci. 273, 1399–1405 19 Little, T.J. et al. (2003) Maternal transfer of strain-specific immunity in an invertebrate. Curr. Biol. 13, 489–492 20 Koella, J.C. (1998) The malaria parasite, Plasmodium falciparum, increases the frequency of multiple feeding of its mosquito vector, Anopheles gambiae. Proc. Biol. Sci. 265, 763–768 21 Scholte, E-J. (2006) Infection of the malaria mosquito Anopheles gambiae with the entomopathogenic fungus Metarhizium anisopliae reduces blood feeding and fecundity. J. Invertebr. Pathol. 91, 43–49 22 Bull, J.J. (1994) Virulence. Evolution Int. J. Org. Evolution 48, 1423– 1437 23 Gu, W. and Nowak, R.J. (2005) Habitat-based modeling of impacts of mosquito larval interventions on entomological inoculation rates, incidence, and prevalence of malaria. Am. J. Trop. Med. Hyg. 73, 546–552 24 Killeen, G.F. (2002) Eradication of Anopheles gambiae from Brazil: lessons for malaria control in Africa? Lancet Infect. Dis. 2, 618–627 25 Phillips, R.S. (2001) Current status of malaria and potential for control. Clin. Microbiol. Rev. 14, 208–226 1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2008.02.004 Available online 9 April 2008
Research Focus
New insight into the role of dendritic cells in malaria immune pathogenesis Stephanie Bousheri and Huyen Cao California Department of Public Health, 850 Marina Bay Parkway, Richmond, CA 94804, USA
The mechanism by which the host develops protective immunity to malaria remains poorly understood. Dendritic cells (DCs) are central to the initiation and regulation of the adaptive immune response. Modulation of DC function might enable Plasmodium to evade the immune system. Millington et al. propose one mechanism by which malaria inhibits DC–T-cell interactions without interfering directly with T-cell receptor engagement. The consequence is a decrease in the co-stimulation required to develop an effective immune response.
leads to an effective immune control of the parasite, but their excessive production will result in severe clinical disease or death [1]. Malaria infection can also suppress the generation of antimalarial immune responses [2–4]. The suppression is thought to be mediated through apoptosis, parasite inhibition of macrophage activation and antigen processing and, more recently, through their inhibition of dendritic cell (DC) maturation or alteration of DC function [5,6]. These inhibitory mechanisms probably include the activation of the presenting DC.
Immunity to malaria infection is elusive Malaria is a devastating disease caused by the Plasmodium parasite, which kills nearly 3 million people and infects more than 400 million each year. Knowledge of the mechanisms leading to protective immunity is surprisingly limited. The optimal immune response to malaria infection involves early proinflammatory, cytokine-mediated, effector mechanisms that clear parasite-infected cells, which are then suppressed equally rapidly by anti-inflammatory effectors once parasite replication has been brought under control [1]. The immune mechanisms that control and kill the parasite are also implicated in subsequent immunopathology. Thus, a potent and timely response of inflammatory cytokines
DCs mediate the adaptive immune response DCs initiate the immune response by providing antigenic stimulation for T and B cells. DCs provide a crucial link between the innate and adaptive immune response and are specialized in the uptake, processing and presentation of antigens to T cells. These antigens are presented in the context of major histocompatibility complex (MHC) class II to T cells along with CD80/CD86 co-stimulations. DCs are the only antigen-presenting cells (APCs) that can activate naı¨ve T cells [7]. The activated T cells are then able to produce cytokines that promote the maturation of the cellular responses directly and help B cells produce antibody. These interactions initiate a cascade of cellular and molecular events that lead to an effective adaptive immune response. The precise nature of the DC–parasite inter-
Corresponding author: Otti, O. ([email protected]).
199
Update action in malaria thus has important consequences for both immunopathology and immunity. Malaria modulates the activation and function of DCs directly (reviewed in Ref. [8]), although controversies remain regarding the effect of infection on the biology of DCs. To function effectively as APCs, DCs undergo a process of maturation, characterized by increased expression of co-stimulatory markers, MHC and adhesion molecules, as well as the secretion of proinflammatory cytokines (reviewed in Ref. [9]). Activation and maturation of DCs during Plasmodium infection has been reported [10–16]. Infected red-blood cells (iRBCs) activate human plasmacytoid DCs [17], possibly through the action of hemozoin (HZ) [18], a by-product of a malaria infection, which appears to target Plasmodium falciparum DNA to intracellular Toll-like receptor 9 receptors [19]. Others, including Millington et al., have demonstrated that DC functions are impaired and suppression might be mediated by HZ [20,21]. HZ has been associated with decreased expression of MHC class II molecules as well as other co-stimulatory molecules, such as CD80 and CD40 [20,22], and inhibition of monocytes [20,22]. The apparent Plasmodium-induced DC suppression in some studies and activation in others might clearly reflect differences in the Plasmodium species studied, distinct DC subsets, or experimental methodologies (reviewed in Refs [15,23]). Millington et al. described findings whereby HZ-loaded DCs were unable to form stable interactions with T cells, failed to induce upregulation of CD40 and reduced the subsequent responsiveness to lipopolysaccharide stimulation [24]. The video accompanying the Millington et al. study of the multi-photon laser-scanning microscopy findings are visually striking. Images of fluorescent-labeled DCs and T cells were acquired sequentially to define the proportion of DCs in contact with T cells in the presence or absence of HZ or Plasmodium-infected RBCs. HZ-treated DCs accumulate the pigments rapidly and fail to form stable clusters with T cells; this results in decreased proliferation. Decreased T-cell motility and cluster formation was evident in the presence of in vitro HZ or in vivo P. chaubaudi. This impaired interaction does not appear to involve the processing and presentation of the antigen in the MHC–T-cell receptor context. Instead, the immediate cellular interaction is altered, such that stable clusters do not form, leading to an abnormal T-cell response. Implications of DC interactions with T cells A conclusive effect of malaria on the biology of DCs is difficult to ascertain, perhaps because of the complexity of the parasite and the DC system. The controversy as to whether DC function is altered uniformly by the malaria parasite might also relate to the abundance of different species of human and rodent Plasmodium and the distinct research approach and methodologies. Demonstration of whether the decreased clustering described by Millington et al. is the normal spectrum of inflammatory and immune response or whether the malaria parasite has evolved specific strategies to actively circumvent an appropriate T-cell response is necessary to further elucidate this interaction. Nevertheless, new insight into the mechanism of suppression has now been provided as one means by which 200
Trends in Parasitology Vol.24 No.5
P. falciparum–DC interactions might influence subsequent antimalarial immunity. References 1 Artavanis-Tsakonas, K. et al. (2003) The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology. Clin. Exp. Immunol. 133, 145–152 2 Riley, E.M. et al. (1989) CD8+ T cells inhibit Plasmodium falciparuminduced lymphoproliferation and gamma interferon production in cell preparations from some malaria-immune individuals. Infect. Immun. 57, 1281–1284 3 Wipasa, J. et al. (2001) Apoptotic deletion of Th cells specific for the 19kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection. J. Immunol. 167, 3903–3909 4 Luty, A.J. et al. (2000) Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect. Immun. 68, 3909–3915 5 Urban, B.C. et al. (1999) Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400, 73–77 6 Urban, B.C. and Roberts, D.J. (2003) Inhibition of T cell function during malaria: implications for immunology and vaccinology. J. Exp. Med. 197, 137–141 7 Banchereau, J. and Steinman, R.M. (1998) Dendritic cells and the control of immunity. Nature 392, 245–252 8 Wykes, M. et al. (2007) Dendritic cell biology during malaria. Cell. Microbiol. 9, 300–305 9 Reis e Sousa, C. (2006) Dendritic cells in a mature age. Nat. Rev. Immunol. 6, 476–483 10 Leisewitz, A.L. et al. (2004) Response of the splenic dendritic cell population to malaria infection. Infect. Immun. 72, 4233–4239 11 Coban, C. et al. (2002) Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine. Infect. Immun. 70, 3939–3943 12 Newman, K.C. et al. (2006) Cross-talk with myeloid accessory cells regulates human natural killer cell interferon-gamma responses to malaria. PLoS Pathog. 2, e118 13 Ing, R. et al. (2006) Interaction of mouse dendritic cells and malariainfected erythrocytes: uptake, maturation, and antigen presentation. J. Immunol. 176, 441–450 14 Perry, J.A. et al. (2004) Dendritic cells from malaria-infected mice are fully functional APC. J. Immunol. 172, 475–482 15 Sponaas, A.M. et al. (2006) Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-specific T cells. J. Exp. Med. 203, 1427–1433 16 Wilson, N.S. et al. (2006) Systemic activation of dendritic cells by Tolllike receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat. Immunol. 7, 165–172 17 Pichyangkul, S. et al. (2004) Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J. Immunol. 172, 4926–4933 18 Coban, C. et al. (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. 201, 19–25 19 Parroche, P. et al. (2007) Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc. Natl. Acad. Sci. U. S. A. 104, 1919–1924 20 Skorokhod, O.A. et al. (2004) Hemozoin (malarial pigment) inhibits differentiation and maturation of human monocyte-derived dendritic cells: a peroxisome proliferator-activated receptor-gamma-mediated effect. J. Immunol. 173, 4066–4074 21 Millington, O.R. et al. (2006) Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. J. Biol. 5, 5 22 Skorokhod, O. et al. (2005) Role of 4-hydroxynonenal in the hemozoinmediated inhibition of differentiation of human monocytes to dendritic cells induced by GM-CSF/IL-4. Biofactors 24, 283–289 23 Langhorne, J. et al. (2004) Dendritic cells, pro-inflammatory responses, and antigen presentation in a rodent malaria infection. Immunol. Rev. 201, 35–47 24 Millington, O.R. et al. (2007) Malaria impairs T cell clustering and immune priming despite normal signal 1 from dendritic cells. PLoS Pathog. 3, 1380–1387 1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2008.02.003 Available online 9 April 2008