Animal models of tuberculosis

ARTICLE IN PRESS Tuberculosis (2005) 85, 277–293

Tuberculosis http://intl.elsevierhealth.com/journals/tube

Animal models of tuberculosis U.D. Gupta, V.M. Katoch Central JALMA Institute for Leprosy & other Mycobacterial Disease (ICMR), P.O. Box No. 101, Tajganj, Agra 282001, India

KEYWORDS Resistance; Genotype; Virulence; Pathogenesis; Bacteraemia; Cytokines; Cell phenotypes

Summary It was Robert Koch who recognized the spectrum of pathology of tuberculosis (TB) in different animal species. The examination of clinical specimens from infected humans and animals confirmed the variable patterns of pathological reactions in different species. Guinea pigs are innately susceptible while humans, mice and rabbits show different level of resistance depending upon their genotype. The studies of TB in laboratory animals such as mice, rabbits and guinea pigs have significantly increased our understanding of the aetiology, virulence and pathogenesis of the disease. The introduction of less than five virulent organisms into guinea pigs by the respiratory route can produce lung lesions, bacteraemia and fatal diseases, which helped the extrapolation of results of such experiments to humans. The similarities in the course of clinical infection between guinea pigs and humans allow us to model different forms of TB and to evaluate the protective efficacy of candidate vaccines in such systems. The only limitation of this model, however, is a dearth of immunological reagents that are required for the qualitative and quantitative evaluation of the immune responses, with special reference to cytokines and cell phenotypes. Another limitation is the higher cost of guinea pigs compared with mice. The rabbit is relatively resistant to Mycobacterium tuberculosis, however following infection with virulent Mycobacterium bovis, the rabbit produces pulmonary cavities like humans. The rabbit model, however, is also limited by the lack of the immunological reagents. Mice are the animal of choice for studying the immunology of mycobacterial infections and have contributed much to our current understanding of the roles of various immunological mechanisms of resistance. The resistance of mice to the development of classic TB disease, however, represents a significant disadvantage of the mouse model. Although nonhuman primates are closely related to humans, owing to high cost and handing difficulties they have not been exploited to a large extent. As all existing animal models fail to mimic the human disease perfectly, efforts should be focused on the development of the non-human primate(s) as the alternative animal model for TB. & 2005 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +91 562 2331946.

E-mail address: [email protected] (U.D. Gupta). 1472-9792/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tube.2005.08.008

ARTICLE IN PRESS 278

Introduction Tuberculosis (TB) caused by Mycobacterium tuberculosis is the leading bacterial cause of death. TB remains a global threat to public health, with approximately 2 million people dying from M. tuberculosis infections every year and one-third of the world’s population latently infected with M. tuberculosis. Every year, 8 million individuals develop active disease.1 In India, TB remains one of the most pressing health problems, accounting for 30% of the global cases.2 It has been estimated in India that every year 2 million people develop TB and nearly 25% of them succumb to the disease, accounting for more than 1000 deaths every day. A vaccine against TB was developed about 80 years ago; various drugs for the control of the disease were developed about 40–50 years ago and combination chemotherapy has been in place for about 2 decades. Yet today we do not seem to be any closer to eliminating TB than we were a century ago. Complete eradication of TB requires a vaccine that is cost effective and can be used for mass immunization. BCG (live attenuated Mycobacterium bovis BCG), the only TB vaccine presently being used, has succeeded only in some countries but has shown very limited usefulness in countries like India. It is the most widely used of all the vaccines in the WHO Expanded Programme for immunization,3 but has been estimated to prevent only 5% of all potentially vaccine-preventable deaths due to TB.4 It has been found to be protective against disseminated and meningeal TB in young children.5 The protective efficacy of BCG vaccine against adult pulmonary TB has varied widely in different geographical areas and different populations.6 Thus, a TB vaccine that protects consistently against adult TB in all populations is needed. Emergence of drug resistance has also led to renewed interest in development of alternate drug formulations. To study alternate modes of treatment and new vaccines and to better understand the host–parasite relationship, animal models are necessary. In the present article, we discuss the different animal models currently available for TB, and propose improvements of the existing models.

Mouse model Robert Koch, who discovered the tubercle bacillus, first used the mouse as an experimental model. He showed that inoculation with M. tuberculosis induced lesions like those seen in the natural disease in humans.7 Subsequently, investigators

U.D. Gupta, V.M. Katoch established infection in a variety of animals (rabbits, guinea pigs, rats and mice) with pure cultures of M. tuberculosis. Due to interest in progressive pulmonary infection, these studies tended to involve guinea pigs and rabbits because of their higher susceptibility to the disease.7 Subsequently, the pioneering work of Browning and Gulbransen8 began to define the pattern of disease in the more resistant mouse model, while an appreciation of this model for investigating the strong immune response to TB that mice obviously possessed also began to emerge slowly.9 During the 1940s, when the first effective chemotherapy for TB was under development, a number of workers realized the importance of the mouse model as a cost-effective model for evaluation of drugs.10,11 McKee et al.12 suggested that the mouse model was more accurate as a measure of drug efficacy than other models such as the guinea pig. In a series of experiments, Dubos and Pierce13 and Pierce et al.14 demonstrated that mice vaccinated with a number of sub-strains of BCG were resistant to TB. Collins and Mackaness15 worked out the relationship between protective immunity and tuberculin sensitivity, while Lefford16 developed the mouse model of adoptive immunity (passive cell transfer). During the last three decades, much information from mouse models has become available that has helped to build the concept that acquired immunity to TB is mediated by T-cells that secrete cytokines which further activate parasitized macrophages and accumulating mononuclear phagocytes.17–20 Monitoring the course of TB infections in mice using a series of techniques has been nicely described by Brown.21 Other relevant technical advances for studying the course of infection in animals during the last few decades are: (i) techniques for growing bacteria in liquid media22; (ii) development of reproducible methods for counting bacterial colonies on solid agar23,24; (iii) the influence of the choice of culture conditions on the virulence of cultures of M. tuberculosis25,26; and (iv) improved methods for bacterial storage.27,28 The virulence of a given strain of M. tuberculosis depends extensively on experimental conditions such as the route of infection,26,29 the manner of preparation of the suspension, and the dispersion and size of the suspension.30 Some host-associated factors such as severe malnutrition, stress, terminal cancer, diabetes, kidney failure, degenerative lung disease and chronic vitamin D deficiency can also influence virulence.31,32 Malnutrition is an important risk factor for TB because it affects cell-mediated immunity (CMI), which is the key host defence against TB (Table 1). Early studies

ARTICLE IN PRESS Animal models of tuberculosis Table 1

279

Comparison of tuberculosis in laboratory animals.

Characteristics

Mice

Guinea pig

Rabbit

Monkeys

Cell-mediated immunity (CMI) Caseation (caseous tissue necrosis) Spread of disease

Good

Poor

Good

Poor

Little

Much

Moderate

Much

Confluent granulomas eventually causing death

Haematogenous spread; lungs destroyed by continuing caseous necrosis

Disease heals, except for cavity formation and bronchial dissemination

Haematogenous spread; lungs destroyed by continuing caseous necrosis

Source: Dannenberg and Collins.187

established that moderate, chronic deficiencies of protein and other nutrients, e.g. zinc, could be induced in guinea pigs and that the resulting nutritional states had many of the metabolic hallmarks of human dietary deficiencies.33,34 Chan et al.,35 using a high-dose intravenous challenge model in mice kept on low protein levels, observed T-cell defects including loss of control of virulent infection and impaired granuloma formation as well as recovery of resistance following re-feeding with an adequate diet. They suggested that loss of resistance to TB in their model was a result of diminished nitric oxide production by activated macrophages that occurred secondary to an IFN-g defect in malnourished animals.36 Similar effects were observed in protein-deficient guinea pigs infected under much more relevant conditions (i.e. low-dose aerosol exposure).33,34,37–39 The growth of M. tuberculosis in mice has been well characterized.18 Infection gives rise to highly characteristic distribution patterns in target organs.30,40 The intravenous and aerogenic routes of infection are most commonly used. The course and rate of mycobacterial infections are modulated by a number of factors,41 including: (i) The virulence of the organism: This involves a number of factors, but these are poorly defined in the case of M. tuberculosis. The lipoglycans of tubercle bacilli are interesting, as they can induce cytokine production by infected macrophages and can influence their ability to scavenge oxygen radicals.42 (ii) The organ in which bacilli are lodged: Bacilli in the liver do not multiply as fast as in the spleen. Another aspect is that bacteria may infect phagocytic cells in the lungs and kidney tissues.43 These bacteria only grow in immuno-competent mice but may eventually cause abscesses. (iii) The size of the inoculum: There is an inverse relationship between the inoculum size and

the delay before the inoculum grows in the mouse to a size that triggers acquired immunity.44 (iv) The intensity of the immune response: Different strains of mice have long been known to have different innate resistance to tuberculous challenge.45,46 Medina and North identified susceptibility variations in several inbred mouse strains. They related such differences to bcg gene (Nramp1) and histocompatibility complex haplotype effects47,48 and classified six inbred mouse strains as either highly susceptible (CBA, DBA/2, C3H and 129/SvJ) or highly resistant (BALB/c and C57BL/6). There is a clear difference between mouse strains infected with a very low dose of the Montreal strain of BCG.49 In some mouse strains, the bovine type of tubercle bacillus, showing different survival times after aerosol and intravenous inoculation, does not multiply in the lungs to higher levels than the human type. But the bovine strain (Ravenel) kills the mice more quickly than the human strain (H37Rv) does. It was concluded that H37Rv components were easier to destroy, although the lesions of each group had identical numbers of bacilli. These persisting antigens caused a rapid increase in size of the granulomas42,43 and caused an early death.42–44 The genetic differences among various inbred strains of mice influence the course of disease. The number of viable H37Rv bacilli in the lungs of BALB/ c mice was 2 log lower than their number in DBA/2 mice during the stationary phase after intravenous injection. The mice of BALB/c and C57BL/6 strains survived twice as long as DBA/2 and C3H/HeJ strains.45 Similarly, the knockout (KO) mice (lacking genes for acquired immune response) show higher bacillary titres during the stationary phase.46,47 Chackerian et al.48 proposed that mycobacteria

ARTICLE IN PRESS 280 seemed to disseminate earlier from the lungs of resistant mice than from those of susceptible mice, which was associated with a stronger response shown by the former. Furthermore Turner et al.50 demonstrated that the inability of reactivationprone mice to recruit lymphocytes to the infection site may underlie their predisposition to chronic infection control failure and associated bacterial regrowth. F1 progeny of susceptible (I/St) and resistant (A/Sn) parental strains have shown an infection hyper-resistant intermediate phenotype providing a better defence against TB.51 The identification of the genetic basis of susceptibility to TB has provided deeper insights into immunopathological aspects,49,52,53 and the link to the tbs1 and tbs2 loci has suggested the existence of a basic genetic network for the control of intracellular parasites.54 After the inhalation of virulent tubercle bacilli, the number of viable bacilli in the lungs of mice also becomes more or less constant after 3–6 weeks.55–57 Tuberculous mice show little necrosis before the final stages of the disease are reached and the animals develop only weak sensitivity to tuberculin. Mice inhaling virulent bacilli die from a progressive enlargement of pulmonary granulomatous tubercles.58 During the stationary growth phase, the mouse controls intracellular multiplication of the bacilli within poorly activated macrophages by killing the macrophages without affecting the neighbouring tissues.58–60 The killing of bacilli-filled macrophages appears to be an integral part of acquired resistance of mice to this infection, although their lesions show little or no necrosis. In mice, there is no direct damage to the surrounding lung tissue, although necrosis does occur when the pulmonary lesions contain a large number of bacilli.

TB in immunodeficient mouse models Because immunity to TB is T-cell mediated, the nude mouse and severe combined immunodeficiency (SCID) mouse that cannot produce T-cells are of interest as models in TB. The nude mouse is furless and suffers from thymic aplasia. These mice cannot produce functional T-cells, therefore they have substantially less resistance to TB and other mycobacterial infections. On the other hand, SCID mice lack both T- and B-cells owing to a defect in the variable region gene recombination61 and lack resistance like nude mice against TB and mycobacterial infections. Both these models are being used to

U.D. Gupta, V.M. Katoch test the capacities of isolated cell populations to protect against mycobacterial infections. The thymectomized (TXB) mouse is the other model, in which the thymus is removed at 4 weeks of age and, after 1 week of recovery, the mouse is exposed to a dose of ionizing radiation to kill all dividing cells including bone marrow cells. The mouse is then reconstituted with the infusion of bone marrow cells. These TXB mice are less resistant to an intravenous M. tuberculosis infection owing to a deficiency of T-cells.62 A recent further development of the TXB model is the TxCD4-mouse model, a TXB, CD4 T-cell deficient mouse.63 This model involves thymectomy followed by infusion of monoclonal and CD4 antibody. This model seems to be efficient in that as little as 200–250 mg of purified antibody can cause severe CD4 depletion.

Gene-disrupted and transgenic mice A new model of TB using targeted gene disruption was developed by Dalton et al.64 In this model, the IFN-g gene was specifically disrupted by the insertion of a neomycin resistance gene after the second exon. Mice in which the IFN-g gene has been disrupted (IFN-g / ) are unable to control a normally sublethal dose of M. tuberculosis, delivered either by intravenous or aerosol route. These IFN-g KO mice have been shown to be extremely susceptible to M. tuberculosis, and a progressive and widespread tissue destruction and necrosis associated with very high numbers of acidfast bacilli are observed.65–67 CD4 T-cell KO (CD4 / ) mice are used as a model for studying the role of CD4 T-cells in the anti-TB response and can mimic HIV infection in humans.68 Using CD4 / mice, Serbina et al.69 demonstrated that the cytotoxic activities of CD8+ T-cells from the lungs of M. tuberculosis-infected mice are impaired while IFN-g production by CD8+ T-cells of CD4 / mice and wild-type mice is comparable. The IL-12 / mice fail to control M. tuberculosis growth in organs. Cooper et al.66 demonstrated marked reduction in T-cell activation and lymphocyte accumulation at the site of infection. IL-12 (70–75 kDa heterodimer IL-12p70) consists of disulfide-bound 35 and 40 kDa subunits. Holscher et al.70 and Cooper et al.71 reported that IL-12p35 / p40 / are highly susceptible to M. bovis (BCG) or M. tuberculosis infection while IL-12p35 / mice showed a reduced susceptibility to pulmonary M. tuberculosis infection. IL-6 KO mice (IL-6 / ) showed a marked decrease in the resistance against

ARTICLE IN PRESS Animal models of tuberculosis virulent M. tuberculosis H37Rv, but not against M. bovis (BCG). Intravenous infection with 106 M. tuberculosis led to a median survival of 59 days in IL-6 / mice while wild-type mice survived for more than 200 days.72 The spleen cells of infected IL-6 / mice produce an increased level of IL-4 and reduced level of IFN-g. Sugawara et al.73 used IL1R1 KO mice for infection with M. tuberculosis and observed significantly larger granulomatous lesions with neutrophil infiltration in their lungs compared with the wild type. Further, the bacterial load in the lungs and spleens increased 5 weeks after infection and IFN-g levels of spleen cells was low in IL-1R1 KO mice. Another mouse strain with a disrupted gene for 55 kDa TNF-a was used in a model for TB.74 It demonstrated that 55 kDa TNF-a was essential for protection of mice against TB as well as for the reactive nitrogen production by macrophages early in infection. Necrosis was observed in the lungs in those mice deficient in TNF-receptor or TNF-a, suggesting that the 55 kDa TNF receptor and TNF-a were essential for protection against murine M. tuberculosis infection. Roach et al.75 had shown that lymphotoxin-a was also required for protecting the host against BCG and M. tuberculosis infection. The burden of bacteria was higher in the lungs and survival time was less in nitric oxide synthatase KO mice (NOS2 / ) when infected with M. tuberculosis H37Rv or Erdman compared with wild type.76 Mice homozygous for Prkdcscid mutations lack both T- and B-cells and were used for examining the relationship between immunity and disease. Mills et al.77 reported that SCID mice with BALB/c background had a severe defect in TB defence as they could not control even the intravenous infection of M. bovis BCG. The role of Toll-like receptors (TLRs) in the development of TB infection has been studied in TLR2-deficient KO mice (TLR2 / ) in BALB/c mice and in TLR4 defective C3H/HeJ mice.78 It was reported that the course of TB infection, granuloma formation, macrophage activation, and secretion of pro-inflammatory cytokines in response to low-dose aerosol infection (100 cfu) of M. tuberculosis was identical in mutant and control groups. But following a high-dose challenge (2000 cfu), TLR2 mice were more susceptible than control mice.

Immunosenescent mice Another form of immunodeficiency is the decline in immunological response with age. It was observed that young mice infected intravenously with a sub-

281 lethal dose (105) of M. tuberculosis bacilli could contain and control infection but that the same dose was fatal in mice of 24–28 months age.79 Initially, it was thought that this mortality was due to lack of protective T-cells in old animals, however Orme80 showed that T-cells that are capable of recognizing mycobacterial antigens in old animals have negligible expression of adhesion homing markers like L-selectin and CD11a and hence focus poorly at infection sites.

Immunology of TB in the mouse model It has become clear from the research of the last few years that all three subsets of T-cells, namely CD4, CD8 and gd T-cells, play a crucial role in the acquired cellular immune response to experimental M. tuberculosis infection in the mouse.20 The use of gene-disrupted mice70,81 confirmed the role of CD4+ T-cells in the murine model. The main role that the CD4+ T-cell population plays in the combat against the pathogen is secretion of the cytokine IFN-g. Other cytokines that activate macrophages play the role of secondary effector molecules. Besides the production of IFN-g and other cytokines, CD4+ T-cells have been implicated in other important roles in controlling infection. This assumption has been corroborated by the finding that gradual depletion of CD4+ T-cells by the use of anti-CD4 antibodies in a murine model of chronic persistent TB resulted in rapid reactivation of infection even though IFN-g levels remained similar in CD4+ depleted and control mice. Further, there was no change in macrophage number or activity in the CD4+ T-cell-depleted mice.82 The role of CD8+ T-cells in controlling TB has been well established. CD8+ cells peak at about a month into experimental infection, ensuring that cell lysis and bacterial release occur after an intact, extensive granuloma has formed at the site of infection, making it unlikely that the bacteria can escape.83 The role of CD8+ cells in controlling TB was confirmed by experimental work involving adoptive transfer84,85 or antibody depletion in mice.86 Both Th-1 and Th-2 responses occur in mice infected with TB—early appearance of Th-1 cells results in protective immunity87,88 by releasing IFNg and other cytokines while the Th-2 response drives antibody production to accumulating antigens processed from dead bacteria. Since the Th-1 and Th-2 responses cross-regulate each other, an enhancement in type-2 immunity would be expected to be detrimental to host resistance.

ARTICLE IN PRESS 282 However, Jung et al.89 reported that IL-10 genedeleted mice incapable of generating a Th-2 response were no more resistant than wild-type mice following M. tuberculosis infection. There are a number of advantages of using a mouse model for TB. Like most humans, mice are able to generate a strong immune response to M. tuberculosis. They are generally resistant to lowdose inocula and can contain the infection without developing active, disseminated disease. Further, like humans, mouse infection is likely to recrudesce as the animal grows old. The murine model is well characterized from the standpoint of immunogenetics, and a large number of immunological reagents are available for all the parameters. This model has come a long way in establishing the role of various immunological mechanisms, including that of Th-1/Th-2 paradigm, and the role of CD4+ and CD8+ T-cells. However, the concept of a ‘‘rational’’ animal model of TB is based upon the selection of a test system that mimics the important aspects of human disease. The resistance of mice to TB disease, however, represents one of the significant disadvantages of the mouse model.

Modelling persistence and reactivation in the mouse Little is known about the basic mechanism involved in maintaining a latent M. tuberculosis infection or the causes of reactivation. In large part, this is due to the difficulty in developing and manipulating an animal model of latent TB. The design of an adequate animal model of latent M. tuberculosis infection is hampered by lack of knowledge about the biological characteristics of both the tubercle bacilli and host immunity during human latent TB. Two murine models of latent M. tuberculosis have been developed. The first mouse model of latent TB (Cornell model) was first developed by McCune and Tompsett.90 Mice were challenged intravenously with 1  106–3  106 viable bacilli of H37Rv strain of M. tuberculosis and then treated with isoniazid (INH) and pyrazinamide beginning within 20 min of infection. Mice thus treated had been apparently sterilized, as they harboured no culturable tubercle bacilli at the time of completion of treatment. However, 90 days after cessation of antibiotics, almost one-third of the mice yielded INH-sensitive bacilli upon organ culture. The drug-induced model of latent TB has the advantage of achieving very low or undetectable numbers of bacilli and maintaining those low levels for many weeks, like latent infection in humans, but has the disadvantage of

U.D. Gupta, V.M. Katoch artificially inducing latency. A modified Cornell model was developed by Flynn et al.91 by modulating the M. tuberculosis inoculum, the duration of antibiotic therapy, the antibiotic dosages, and the interval between cessation of antibiotics and immunologic intervention. A variety of immunosuppressive agents, based on immunologic factors known to be important to control acute infection, were used to reactivate the infection. They reported that although reactivation of latent infection occurred, these models were associated with characteristics that limit their experimental utility, including spontaneous reactivation, difficulties in inducing reactivation, and the generation of altered bacilli.

Guinea pig model of TB In the 1800s and 1900s, the guinea pig was the most widely used experimental animal for infectious disease studies. The classic experiments that established a microorganism as the aetiological agent of TB were carried out with guinea pigs infected with M. tuberculosis.92 Koch’s principle reason for choosing this species for studies of M. tuberculosis in those days is still valid today—the susceptibility of this species to infection with human tubercle bacilli.93 Sisk94 outlined a number of remarkable similarities between guinea pigs and human beings. Many of these similarities have direct or indirect bearing on the relevance of the guinea pig species as a model for human infectious disease. The main similarities between the two species are: (i) newborn guinea pigs possess a very mature lymphomyeloid complex, like human infants95; (ii) hormonally and immunologically, guinea pigs are closer to humans than rodents are96; (iii) guinea pigs require an exogenous supply of ascorbic acid (vitamin C) in the diet, like human beings97; (v) guinea pigs are corticosteroid-resistant like, humans and non-human primates98; (v) there are striking similarities in the physiology of the pulmonary tract, especially the response of lung to inflammatory stimuli, between guinea pigs and humans.99 Guinea pigs have been extensively used in testing both of biological reagents and drugs against TB. This animal has been the gold standard for potency testing and biological standardization of tuberculins for use in human skin testing.100,101 Similarly, the development and pre-clinical testing of BCG vaccines by Calmette et al.102 was mainly based on guinea pigs. Smith et al.103 tested the quality

ARTICLE IN PRESS Animal models of tuberculosis control procedures (to ensure continued attenuation of BCG) and variable potencies of BCG vaccines in guinea pigs. Guinea pigs respond quite well to anti-TB antibiotics, and this model has been successfully used to test the efficacy of new drugs or drug combinations.104,105 With the rise of multi drug-resistant strains of M. tuberculosis, this model will be of prime importance in the search for new and efficient antimycobacterial drugs.106 The most promising new drug candidate to appear in decades (PA-824) was shown to be efficacious in the guinea pig model of low-dose pulmonary infection.107 During the last 50 years, the guinea pig model has been of great help in understanding the fundamental relationship between the tubercle bacilli and its human host. Very early studies on the pathogenesis of experimental TB in vaccinated and non-vaccinated guinea pigs showed that previous exposure to mycobacterial antigens often caused delayed hypersensitivity and an inability to reduce the accumulation of tubercle bacilli in the tissues.108–110 Similarly, the interaction between nutritional deficiencies (protein, vitamins C and D) and resistance to experimental TB has also been studied by a number of workers.37–39,111 McMurray et al.112 reported that BCG-vaccinated guinea pigs maintained on a low protein diet during the entire 6-week post-vaccination period, but given a normal diet beginning on the day of virulent pulmonary challenge, displayed PPD skin test reactivity and vaccine-induced control of bacillary loads in the lungs and spleens that were indistinguishable from BCG-vaccinated animals that had never been protein-deficient.112 Other studies of the interaction between tubercle bacilli and host phagocytic cells113 and the potential role of mycobacterial constituents as virulence factors114,115 were conducted in guinea pigs. Experiments by Riley et al.116 and Middlebrook117 demonstrated that guinea pigs are susceptible both to artificial and natural aerosols containing low levels of virulent M. tuberculosis. The concept of a ‘‘rational’’ animal model of TB was based upon the selection of test system variables that mimic the important aspects of human disease.118,119 Smith and his colleagues demonstrated that guinea pigs could be infected reproducibly even with 1–2 cfu of M. tuberculosis and the viability of the inoculum remained unaltered for several years after storing at 70 1C.120,121 Smith et al.122 used this model to explain the early events in pathogenesis of pulmonary TB. The guinea pig developed primary pulmonary lesions histologically similar to human tubercles following exposure to a few viable tubercle bacilli. The number of bacilli recovered

283 from the lungs increased exponentially between 3 and 21 days post infection (to 105–106 cfu). The first organisms appeared in the bronchotracheal lymph nodes between 14 and 18 days of pulmonary infection and in the spleen at 18–21 days, at which time the guinea pigs began to convert their tuberculin skin tests to positive. Lasco et al.123 reported that when guinea pigs were infected with a low dose of M. tuberculosis via the respiratory route, a high number of eosinophils associated both with resident bronchoalveolar populations and in the lung granulomas. They concluded that the rapid influx of these cells and their subsequent degranulation during acute pulmonary TB might play a crucial role in the susceptibility of this animal model. Vaccination has a dramatic effect on the course and outcome of pulmonary TB in guinea pigs. Many types of vaccines have been tested in this model, including non-viable bacilli,124 attenuated mycobacteria,125 different strains of BCG,103,126–130 recombinant protein/peptide vaccines,127,131,132 and DNA vaccines.133–137 Jespersen138 demonstrated that BCG was quite effective even at very low doses when given by the subcutaneous or intradermal route. Palendira et al.137 also concluded that the protective efficacy of BCG did not depend upon the route of administration. Further, Lagranderie et al.139 concluded that aerosol vaccination with BCG is as effective as parenteral immunization. Two commercially available inbred strains of guinea pigs, strains 2 and 13,140 and an outbred Hartley strain were compared in their responses to low-dose pulmonary infections and no significant differences were observed in lung and spleen bacillary loads 4–6 weeks post infection.141 Prior vaccination of animals with BCG before infection protected animals of all three strains equally. On the basis of these experiments, Cohen and coworkers concluded that inbred guinea pigs may be useful in experiments where syngenic hosts are required.141 Lesion numbers in infected guinea pigs have usually been evaluated by a gross post-mortem examination and histopathology for comparison between treatment groups. These methods are relatively inexpensive and leave the majority of the tissue for additional procedures (such as lung bacterial load) but they have the disadvantage that samples taken may not be representative of the entire lung. Kraft et al.142 used magnetic resonance imaging to visualize lesions in the lungs of guinea pigs infected by low-dose aerosol exposure to M. tuberculosis. The results obtained showed that lung lesions could be clearly visualized

ARTICLE IN PRESS 284 and that application of three-dimensional (3D) stacking could be utilized to give a reconstructed view of the whole lung, allowing an assessment of whole-organ lesion distribution. Malnutrition has been known for a long time to exert a deleterious effect on T-cell-mediated immune response.143 The impact of chronic, moderate dietary protein deprivation on resistance to TB was examined by McMurray and Yetley144 and McMurray et al.39,145 They concluded that the protein-malnourished guinea pig infected with mycobacteria showed many immunological deficits such as loss of protection following vaccination with BCG.146,147 These results have obvious implications for TB control in malnourished populations. When a histological comparison was made of lungs from normal nourished and malnourished guinea pigs, it was observed that malnutrition interferes with normal granuloma formation, giving rise to smaller, numerous and less well circumscribed tubercles in the lungs of protein-deprived animals. The human and experimental animal literature on the interaction between malnutrition and TB has been recently reviewed by McMurray et al.112 and they have suggested that the malnourished guinea pigs may be a useful model for anergic TB patients.

Modelling other clinical forms of TB Besides primary pulmonary TB, the guinea pig model may be useful for other forms of the disease such as tuberculous pleuritis, exogenous re-infection and endogenous reactivation. Pleuritis can be induced in previously immunized guinea pigs by the intrapleural injection of either living BCG148 or heat-killed M. tuberculosis.149 Phalen and McMurray150 reported enhanced TNF-a levels in effusion fluid as well as in supernatant fluids from pleural fusion lymphocytes stimulated with PPD. Exogenous re-infection has been studied in the guinea pig. Re-infection by the pulmonary route with virulent M. tuberculosis of guinea pigs previously infected with non-tuberculous mycobacteria or low virulence clinical isolates did not exacerbate the disease as has been reported in humans151 but provided protection.152,153 The reinfected guinea pigs responded to the second virulent challenge better than those infected for the first time under identical conditions and the protective effect of a prior pulmonary exposure to a low virulence isolate was significantly impaired by protein malnutrition.154 Endogenous reactivation TB is mostly seen in elderly populations whose primary exposure may

U.D. Gupta, V.M. Katoch have occurred long ago. A model of endogenous reactivation disease would help us in understanding the factors associated with persistence of M. tuberculosis in tissues as well as the events that allow the dormant mycobacteria to become active and grow in large numbers. Although there are limited data on endogenous reactivation in guinea pigs, Smith and Wiegeshaus155 described how such a model can be developed.

Studies of cytokines and chemokines in guinea pigs Several guinea pig cytokine and chemokine genes have been cloned in recent years.156–159 Using Northern blot and real-time RT-PCR methodologies, it was demonstrated that splenocytes from BCGvaccinated guinea pigs stimulated with whole mycobacteria or purified antigens responded with higher levels of IFN-g mRNA.160 BCG vaccination augmented TNF-a protein production in splenocytes, resident peritoneal cells, and bronchoalveolar lavage cells following exposure to virulent and attenuated strains of M. tuberculosis.161 In addition, Lasco et al. produced recombinant guinea pig (rgp) TNF-a and demonstrated that treating infected guinea pig cells alters the cytokine profile.162 Guinea pig macrophages treated with rgpTNF-a produced elevated levels of TNF-a mRNA and protein and expressed enhanced levels of IL12p40 mRNA.163 Studies by Cho et al. revealed that treatment of macrophages infected with either virulent or attenuated strains of M. tuberculosis with anti-rgpTNF-a neutralizing antisera resulted in enhanced accumulation of intracellular mycobacteria.163 Jeevan et al. demonstrated that guinea pig splenocytes and peritoneal macrophages produced less IL-1b mRNA following infection with virulent with compared attenuated mycobacteria.164 The kinetics of TGF-b mRNA production in the pleural effusion cells of guinea pigs following induction of experimental tuberculous pleuritis have been documented.165 Allen et al. observed that neutralization of guinea pig TGF-b by intrapleural injection of antibodies resulted in significant enhancement of mycobacterial antigeninduced lymphocyte proliferation in the pleural effusion lymphocytes.166 Chemokines are involved in the recruitment and activation of inflammatory cells during the onset of granuloma formation following infection with M. tuberculosis. Guinea pig alveolar macrophages produced IL-8 (CXCL8) and MCP-1 (CCL2) mRNA and IL-8 protein following infection in vitro with

ARTICLE IN PRESS Animal models of tuberculosis virulent and attenuated strains of M. tuberculosis, and prior BCG vaccination of guinea pigs enhanced IL-8 production.167 In addition, it was shown that pre-treatment of guinea pig neutrophils with recombinant guinea pig IL-8 (rgpil-8) induced enhanced cytokine and superoxide production following exposure to mycobacteria in vitro.168 RANTES (CCL5) has been shown to attract and activate memory CD4+ T-cells and monocytes/ macrophages. Jeevan et al. demonstrated that guinea pig splenocytes and peritoneal exudate cells produce RANTES mRNA in response to virulent and attenuated mycobacteria, and that prior vaccination up-regulated the production of RANTES mRNA in vitro.164 In addition, Skwor et al. showed that pre-treatment with rgpRANTES stimulated enhanced cytokine responses in various macrophage populations infected with mycobacteria.169 The main limitations of the guinea pig model are: (i) paucity of readily available immunological reagents that are required for the qualitative and quantitative evaluation of the immune responses; (ii) high cost compared with rodents; and (iii) requirement of excellent husbandry practices for this species. However, its biological relevance more than justifies the efforts required to improve the guinea pig model.

Rabbit model of TB In rabbits, TB is a disease in which lung tissue is destroyed, largely as a result of the host’s own reaction to bacillary antigens. The most extensive studies on TB using the rabbit as an experimental model were made by Lurie170–172 and Lurie and Dannenberg.173 Inbred lines of rabbit were developed for resistance and susceptibility to TB. Resistant rabbits developed cavitary TB like adult immunocompetent humans when infected with the virulent Ravenel strain of M. bovis. The susceptible rabbit families developed haematogenously spread TB like human infants and immuno-compromised individuals. Most of the rabbits available commercially have intermediate resistance to TB. Many of them develop cavities when infected with virulent bovine tubercle bacilli but few die of early haematogenous spread of disease. As rabbits are generally not inbred, there is a lot of variability in resistance to tubercle bacilli. Pulmonary TB in rabbits, like humans, has five stages.174,175 Stage I is the ingestion of inhaled bacilli by pulmonary alveolar macrophages (AM). A majority of the AM are highly activated cells that can destroy or inhibit the growth of inhaled bacilli

285 if the bacilli are not virulent. But some AM are poorly activated and allow the ingested tubercle bacilli to multiply intracellularly. These AM finally die and release their bacillary load to be taken up by non-activated macrophages/monocytes from the bloodstream entering the developing tubercle. In stage II (logarithmic phase), the bacilli grow uninhibited within non-activated macrophages. In stage III, tissue-damaging delayed type hypersensitivity kills macrophages that harbour more than a few bacilli in their cytoplasm. As a result, the logarithmic intracellular growth stops and the tubercle’s early caseous centre develops. Tubercle bacilli fail to develop in this solid caseous centre. The killing of macrophages that contain more than a few bacilli is a major host defence mechanism that controls the number of viable bacilli in the host.174,175 Stage IVa occurs in Lurie’s inbred resistant rabbits: the bacilli escape from the edge of the caseous centre and grow intracellularly within the poorly activated macrophages that now surround the caseum. Stage IVb occurs in Lurie’s inbred resistant rabbits: bacilli escape from the edge of the centre but cannot grow intracellularly within highly activated macrophages that now surround the caseum. Stage V is the stage during which the solid caseous centre of the tubercle liquefies where the bacilli can grow extracellularly and can attain large numbers so that the strong CMI developed by the resistant host is overwhelmed. When such liquefied lesions release their contents into the bronchial tree, a cavity forms and the bacilli spread to other parts of the lung and to the environment. Resistance to the establishment of an infectious disease is distinct from resistance to its progress.176–179 ‘‘Establishment’’ refers to the initial multiplication of an infectious agent in the host while ‘‘progress’’ means the agent’s continuous multiplication in the host. Two factors influence resistance to the establishment of TB: (i) the trapping of tubercle bacilli in the lung; and (ii) the initial inactivation of these bacilli. The trapping is somehow dependent on the alveolar macrophages to phagocytize the bacilli. It has been seen in vitro that the cells of some resistant rabbits were able to ingest twice as many bacilli compared with AM from certain susceptible rabbits.180 These results suggest why certain resistant rabbits developed TB sooner compared with the susceptible rabbits when both were infected in a closed room over a period of many months.176 For every inhaled human-type tubercle bacillus that led to lesion development, many inhaled bacilli were inactivated.178–182 The inactivation of bacilli was enhanced in resistant rabbits compared with

ARTICLE IN PRESS 286 susceptible rabbits. Thus, resistant rabbits resisted the establishment of primary lesions better than susceptible rabbits in spite of trapping more bacilli.181 Lurie and co-workers177,182 have demonstrated the dichotomy between the number of viable bacilli and the progression of the disease in rabbits. They infected innately susceptible and resistant strains of rabbits with aerosols of virulent human- and bovine-type tubercle bacilli. Between 2 and 4 weeks after aerosol infection, the rabbits became tuberculin positive and caseous necrosis developed within the pulmonary lesions. At 3 weeks, the lungs of Lurie’s susceptible rabbits contained six times more viable bovine-type bacilli and 26 times more viable human-type bacilli. The differences between the number of viable bacilli in susceptible and resistant rabbits were primarily due to the early effectiveness of their AM.164,179 Between 4 and 8 weeks, the number of viable bovine-type182 and human-type177 bacilli remained constant both in resistant and susceptible rabbits. The susceptible strains of rabbits died on average about 3 months after inhaling low doses of bovine-type bacilli, while the resistant strains of rabbits survived up to 6 months.172–174,176,181 The susceptible rabbits developed secondary tubercles in the spleen, liver and kidneys after infection with human-type bacilli and the disease (though non-progressive) was still present at 12 months when the resistant rabbits were free from the disease.173,176,182 In native resistant rabbits during the stationary phase of viable bacilli, the tubercle bacilli were also multiplying. Eventually, this multiplication occurred extracellularly in liquefied caseous material,182–184 especially that found in the walls of cavities where higher oxygen levels were present.183,184 In the resistant rabbits, intracellular bacillary growth within macrophages surrounding the caseous centre was minimized as macrophages were activated185 by strong CMI developed by the resistant rabbits.174,178,186 Such activated macrophages, however, failed to control the bacillary multiplication within liquefied caseum in the air-exposed regions of the cavity walls.183,184 With virulent bovine-type bacilli, the large number of extracellular bacilli from the cavities made the host’s strong CMI ineffective in preventing the progression of the disease. Dannenberg and Collins187 concluded that culturing of lung to estimate the number of viable tubercle bacilli is not a good prognostic indicator without studying the gross pathology and histopathology of the lesions. Antigen production and the amount of disease can increase while the number of viable bacilli remains constant because

U.D. Gupta, V.M. Katoch multiplication and death of bacilli may take place at almost equal rates. Further, the disease can still progress in hosts with good immunity owing to uncontrolled multiplication of bacilli within cavities.187 Manabe et al.188 infected rabbits by the aerosol route with M. tuberculosis and observed a spectrum of disease using different strains of M. tuberculosis. Because of the innate resistance of commercial rabbits to tubercle bacilli, 320–1890 log phase actively-growing inhaled bacilli were required to form one grossly visible pulmonary tubercle at 5 weeks. The range of inhaled doses required to make one tubercle may be a measure of the relative pathogenicity of different strains. Fewer inhaled organisms of M. tuberculosis Erdman strain were required than M. tuberculosis H37Rv to produce a visible lesion at 5 weeks. They concluded that the relative pathogenicity, including disease severity, in a rabbit model with strain genotype may help in identifying stage-specific M. tuberculosis genes important in human disease. Dorman et al.189 compared inbred and outbred New Zealand White rabbits infected by aerosol with either M. tuberculosis Erdman or H37Rv strain. Five weeks after infection, the inbred rabbits had significantly larger pulmonary tubercles than outbred animals (2.7 mm versus 1.4 mm in diameter; po0:01). After infection with H37Rv, inbred rabbits had more pulmonary tubercles than the outbreds and more mycobacterial cfu per tubercle. When inbred and outbred rabbits were compared histologically, inbred animals showed more caseous necrosis, more visible bacilli, and fewer epitheleoid cells. They concluded that inbred rabbits were more susceptible to TB than outbred rabbits and had an impaired ability to contain disease, resulting in more grossly visible tubercles that were larger than those observed in outbred rabbits. This animal species provides an excellent laboratory model for TB because it displays a spectrum of disease that represents many specific stages of the human disease.190–192 Resistant rabbits have been shown to develop cavitary TB resembling that found in immunocompetent human beings and the susceptible rabbit families developed haematogenously spread TB resembling that found in infants and immunocompromised individuals. In the era before genomics and before biochemical properties were elucidated, the rabbit model was also used to differentiate between M. bovis and M. tuberculosis because of their remarkable difference in virulence for these animals.193 Unfortunately, the resistant and susceptible inbred rabbits used in all of this work are no longer available. Furthermore, this model suffers from the lack of immunological

ARTICLE IN PRESS Animal models of tuberculosis reagents, the high cost of purchasing and caring for rabbits under BL3 conditions, and extensive BL-3 space required for rabbits compared with an equal number of mice or guinea pigs.

TB in monkeys There are a number of reports that suggest that rhesus monkeys (Macaca mulatta) are highly susceptible to virulent M. tuberculosis and virulent M. bovis.194–197 The disease in monkeys is usually a rapidly progressive pulmonary disease with both haematogenous and bronchial spread of the bacilli. There are reports that suggest extensive caseous necrosis along with liquefaction of the caseous material with cavity formation.194,195,198,199 The walls of the cavities harbour numerous tubercle bacilli198 that spread the disease through the air. Bronchopneumonia, areas of tuberculous pneumonia194,197–199 and enlarged caseous hilar lymph nodes are commonly seen197–199 in infected monkeys. The severity of the disease is reduced when the monkeys are immunized with BCG,195 which can prevent visible pulmonary lesions in some animals if only a few virulent M. tuberculosis are initially inhaled. Walsh et al.200 reported that Philippine cynomolgus monkeys (Macaca fascicularis) were more resistant than rhesus monkeys to infection with virulent human-type tubercle bacilli. They observed development of a chronic, slowly progressing granulomatous disease when monkeys were infected by the intratracheal route with 10–100 bacilli. There was variation in tuberculin skin tests and no cavitation was observed. Though the cynomolgus monkeys appear to be more resistant than rhesus monkeys, they are not as resistant as immunocompetent human beings. McMurray201 reviewed the early literature on experimental primate TB. Langermans et al.202 compared the efficacy of BCG vaccination and course of infection in both rhesus and cynomolgus monkeys. They observed that unvaccinated rhesus and cynomolgus monkeys developed progressive disease with high levels of C-reactive protein, M. tuberculosis-specific IgG, and extensive pathology including cavitation and caseous necrosis. BCG protected cynomolgus monkeys almost completely from the development of pathology, and induced a 2 log reduction in viable bacteria in the lungs compared with unvaccinated animals. Furthermore, rhesus monkeys were not protected efficiently by BCG, as vaccinated animals developed

287 substantial pathology and negligible reduction in bacteria in the lung. Capuano et al.203 infected cynomolgus macaques with low doses of virulent M. tuberculosis via bronchoscopic instillation into the lung. Active chronic infection was observed in 50–60% of monkeys with clear signs of disease on serial thoracic radiography and in other tests. Approximately 40% of monkeys did not progress to disease in the 15–20 months of study although they were clearly infected initially. They conclude that low dose infection of cynomolgus macaques appears to represent the full spectrum of human M. tuberculosis infection and will be an excellent model for the study of pathogenesis and immunology of TB. In addition, this model may provide an opportunity to study the latent M. tuberculosis infection observed in 90% of all infected humans.

Conclusions Non-human primates (monkeys) appear to have significant advantages over conventional laboratory animals in terms of modelling pulmonary TB for the purpose of vaccine evaluation201 as they are closely related to humans, are quite susceptible to infection by the aerosol route, develop human-like disease, exhibit antigen-induced T-lymphocyte activity both in vivo and in vitro, and can be protected quite effectively by BCG. In addition, major advances in availability of immunologic and other reagents for use in macaques, pioneered primarily by those studying simian virus infection in macaques as a model for human immunodeficiency virus infection and AIDS, have made the study of host responses in monkeys feasible. The difficulties (BL3 space requirements, animal availability, high cost of maintenance, handling difficulties and adverse public opinion) and expense of performing TB research with non-human primates limit the widespread use of this model. However, as the existing small animal models fail to mimic the human disease perfectly, serious efforts should be made to develop monkeys as the alternate model for TB.

Acknowledgements I thank Dr. David N. McMurray, Department of Medical Microbiology and Immunology, Texas A & M University System Health Science Center, 407 Reynolds Medical Building, College Station, TX

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77843-1114, USA for critical reading of the manuscript. 22. 23.

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