Differences in reactivation of tuberculosis induced from anti-TNF treatments are based on bioavailability in granulomatous tissue

The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF—even at very low levels—is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNF-modulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely.     

Mycobacterial lipolytic enzymes: A gold mine for tuberculosis research

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide with a strong impact in developing countries. Mycobacterium tuberculosis, the etiological agent of TB, has a high capacity to evade the host immune system and establish a chronic, asymptomatic and latent infection. In a latent TB infection, persistent bacilli are present in a non-replicating dormant state within host granulomas. During reactivation, bacilli start replicating again leading to an active TB infection that can be highly contagious. Mycobacterial lipids and lipolytic enzymes are thought to play important physiological roles during dormancy and reactivation. The role of lipolytic enzymes in the physiology of M. tuberculosis and physiopathology of the disease will be discussed in this review, with an emphasis on the secreted or cell wall-associated, surface exposed lipolytic enzymes characterized to date. Studies on the localization, enzymatic activity and immunological properties of these enzymes highlighted their possible usefulness as new diagnostic markers in the fight against TB.     

The non-human primate model of tuberculosis

Non-human primates (NHPs) are used to model human disease owing to their remarkably similar genomes, physiology, and immune systems. Recently, there has been an increased interest in modeling tuberculosis (TB) in NHPs. Macaques are susceptible to infection with different strains of Mycobacterium tuberculosis (Mtb), producing the full spectrum of disease conditions, including latent infection, chronic progressive infection, and acute TB, depending on the route and dose of infection. Clearly, NHPs are an excellent model of human TB. While the initial aim of the NHP model was to allow preclinical testing of candidate vaccines and drugs, it is now also being used to study pathogenesis and immune correlates of protection. Recent advances in this field are discussed in this review. Key questions such as the effect of hypoxia on the biology of Mtb and the basis of reactivation of latent TB can now be investigated through the use of this model.     

A booster vaccine expressing a latency-associated antigen augments BCG induced immunity and confers enhanced protection against tuberculosis

Background

In spite of a consistent protection against tuberculosis (TB) in children, Mycobacterium bovis Bacille Calmette-Guerin (BCG) fails to provide adequate protection against the disease in adults as well as against reactivation of latent infections or exogenous reinfections. It has been speculated that failure to generate adequate memory T cell response, elicitation of inadequate immune response against latency-associated antigens and inability to impart long-term immunity against M. tuberculosis infections are some of the key factors responsible for the limited efficiency of BCG in controlling TB.

Methods/Principal Findings

In this study, we evaluated the ability of a DNA vaccine expressing α-crystallin- a key latency antigen of M. tuberculosis to boost the BCG induced immunity. ‘BCG prime – DNA boost’ regimen (B/D) confers robust protection in guinea pigs along with a reduced pathology in comparison to BCG vaccination (1.37 log₁₀ and 1.96 log₁₀ fewer bacilli in lungs and spleen, respectively; p<0.01). In addition, B/D regimen also confers enhanced protection in mice. Further, we show that B/D immunization in mice results in a heightened frequency of PPD and antigen specific multi-functional CD4 T cells (3⁺) simultaneously producing interferon (IFN)γ, tumor necrosis factor (TNF)α and interleukin (IL)2.

Conclusions/Significance

These results clearly indicate the superiority of α-crystallin based B/D regimen over BCG. Our study, also demonstrates that protection against TB is predictable by an increased frequency of 3⁺ Th1 cells with superior effector functions. We anticipate that this study would significantly contribute towards the development of superior booster vaccines for BCG vaccinated individuals. In addition, this regimen can also be expected to reduce the risk of developing active TB due to reactivation of latent infection.     

Reactivation of Latent Tuberculosis in Cynomolgus Macaques Infected with SIV Is Associated with Early Peripheral T Cell Depletion and Not Virus Load

HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection.     

Novel recombinant BCG coexpressing Ag85B,ESAT‐6 and mouse TNF‐α induces significantly enhanced cellular immune and antibody responses in C57BL/6 mice

The recent emergence of multidrug‐resistant and extensively drug‐resistant strains of Mtb and the epidemic of TB in populations co‐infected with human immunodeficiency virus demonstrate that TB remains a leading infectious disease. Moreover, the failure of BCG to protect against this disease indicates that new vaccines against TB are urgently needed. Experimental evidence has revealed that TNF plays a major role in host defense against Mtb in both active and latent phases of infection. Release of TNF, which would induce mycobacteria‐mediated macrophage apoptosis and thus reduce the spread of mycobacteria, is one of the most important and early responses of macrophages challenged with Mtb. In order to identify the usefulness of TNF in improving the effectiveness of TB vaccine, in the current study a novel rBCG strain expressing the fusion gene of Ag85B‐Esat6‐TNF‐α in BCG Danish strain was constructed, and its ability to induce an immune response in C57BL/6 mice evaluated. It was found that immunization with strains of rBCG‐Ag85B‐Esat6‐TNF‐α can induce a stronger immune response than does immunization with rBCG‐Ag85B‐Esat6 or parental BCG. The results indicate that rBCG‐Ag85B‐Esat6‐TNF‐α is a promising candidate for further study.     

FasL regulatory B-cells during Mycobacterium tuberculosis infection and TB disease

Tuberculosis (TB) disease remains a major health crisis. Infection with Mycobacterium tuberculosis (M.tb) cause a range of diseases ranging from latent infection to active TB disease. This active state of the disease is characterised by the formation of granulomas (a physical barrier in the lung), a structure thought to protect the host by controlling the infection through preventing the growth of the bacilli. Subsequently, the surviving bacteria become inactive and in most cases, TB reactivation is prevented by the immune response of the host. B-cells perform numerous immunological functions beyond antibody production to positively regulate the response to pathogenic assault. A subgroup of B-cells with regulatory functions express death-inducing ligands, such as Fas ligand (FasL). Expression and interaction of the Fas receptor-ligand promotes the induction of apoptosis and the induction of T-cell tolerance. Here, we focus on the significance of B-cells by addressing their FasL phenotype and regulatory functions during TB, with reference to disease in humans, non-human primates and mice.     

Reactivation of M. tuberculosis infection in trans-membrane tumour necrosis factor mice

Of those individuals who are infected with M. tuberculosis, 90% do not develop active disease and represents a large reservoir of M. tuberculosis with the potential for reactivation of infection. Sustained TNF expression is required for containment of persistent infection and TNF neutralization leads to tuberculosis reactivation. In this study, we investigated the contribution of soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) in immune responses generated against reactivating tuberculosis. In a chemotherapy induced tuberculosis reactivation model, mice were challenged by aerosol inhalation infection with low dose M. tuberculosis for three weeks to establish infection followed chemotherapeutic treatment for six weeks, after which therapy was terminated and tuberculosis reactivation investigated. We demonstrate that complete absence of TNF results in host susceptibility to M. tuberculosis reactivation in the presence of established mycobacteria-specific adaptive immunity with mice displaying unrestricted bacilli growth and diffused granuloma structures compared to WT control mice. Interestingly, bacterial re-emergence is contained in Tm-TNF mice during the initial phases of tuberculosis reactivation, indicating that Tm-TNF sustains immune pressure as in WT mice. However, Tm-TNF mice show susceptibility to long term M. tuberculosis reactivation associated with uncontrolled influx of leukocytes in the lungs and reduced IL-12p70, IFNγ and IL-10, enlarged granuloma structures, and failure to contain mycobacterial replication relative to WT mice. In conclusion, we demonstrate that both solTNF and Tm-TNF are required for maintaining immune pressure to contain reactivating M. tuberculosis bacilli even after mycobacteria-specific immunity has been established.     

Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists

Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-gamma. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-gamma release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-gamma upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.     

针对结核分枝杆菌潜伏感染的DNA疫苗V569免疫原性及保护性的初步研究

为研究针对结核分枝杆菌潜伏感染的DNA疫苗,基于质粒A39构建了p-VAX1-Ag85B-Rv3425-Rv2029c-PPE26 (V569)质粒DNA,并对其免疫原性及保护性进行初步研究。免疫性评价试验共分6组：PBS、p-VAX1-Ag85B(A)、p-VAX1-Ag85B-Rv3425(A3)、A39、V569和BCG,采用左后腿肌内注射C57BL/6小鼠,用流式细胞术和酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)分别检测细胞免疫和体液免疫水平;构建斑马鱼-海分枝杆菌潜伏感染模型,将PBS、A、A3、A39、BCG、V569分别通过腹腔注射免疫斑马鱼后,每日注射地塞米松10ug诱导海分枝杆菌复发感染,对斑马鱼肝脏进行菌落计数并绘制生存曲线。结果显示,与BCG组相比,V569能引发实验小鼠强烈的细胞免疫反应(IFN-γ高水平分泌),外周血CD4^＋/CD8^＋ T细胞比例明显增加。在斑马鱼-海分枝杆菌潜伏感染复发模型中,与BCG 免疫组相比,V569免疫斑马鱼后可显著减少其肝脏中海分枝杆菌数量,斑马鱼存活情况得到显著改善,表明V569 DNA疫苗可能是一种抗结核潜伏感染的候选DNA疫苗。     

Reactivation of latent tuberculosis in rhesus macaques by coinfection with simian immunodeficiency virus

Background Tuberculosis (TB) and AIDS together present a devastating public health challenge. Over 3 million deaths every year are attributed to these twin epidemics. Annually, ～11 million people are coinfected with HIV and Mycobacterium tuberculosis (Mtb). AIDS is thought to alter the spontaneous rate of latent TB reactivation. Methodology Macaques are excellent models of both TB and AIDS. Therefore, it is conceivable that they can also be used to model coinfection. Using clinical, pathological, and microbiological data, we addressed whether latent TB infection in rhesus macaques can be reactivated by infection with simian immunodeficiency virus (SIV). Results A low‐dose aerosol infection of rhesus macaques with Mtb caused latent, asymptomatic TB infection. Infection of macaques exhibiting latent TB with a rhesus‐specific strain of SIV significantly reactivated TB. Conclusions Rhesus macaques are excellent model of TB/AIDS coinfection and can be used to study the phenomena of TB latency and reactivation.     

HspX protein as a candidate vaccine against <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis>: an overview

Background

Tuberculosis (TB) is a contagious infectious disease caused by Mycobacterium tuberculosis (Mtb). This disease with two million deaths per year has the highest mortality rate among bacterial infections. The only available vaccine against TB is BCG vaccine. BCG is an effective vaccine against TB in childhood, however, due to some limitations, has not proper efficiency in adults. Also, BCG cannot produce an adequately protective response against reactivation of latent infections.

Objective

In the present study we will review the most recent findings about contribution of HspX protein in the vaccines against tuberculosis.

Methods

Therefore, many attempts have been made to improve BCG or to find its replacement. Most of the subunit vaccines for TB in various phases of clinical trials were constructed as prophylactic vaccines using Mtb proteins expressed in the replicating stage. These vaccines might prevent active TB but not reactivation of latent tuberculosis infection (LTBI). A literature search was performed on various online databases (PubMed, Scopus, and Google Scholar) regarding the roles of HspX protein in tuberculosis vaccines.

Results

Ideal subunit post-exposure vaccines should target all forms of TB infection, including active symptomatic and dormant (latent) asymptomatic forms. Among these subunit vaccines, HspX is the most important latent phase antigen of M. tuberculosis with a strong immunological response. There are many studies that have evaluated the immunogenicity of this protein to improve TB vaccine.

Conclusion

According to the studies, HspX protein is a good candidate for development of subunit vaccines against TB infection.

     

Tuberculosis and HIV Co-Infection

Tuberculosis (TB) and HIV co-infections place an immense burden on health care systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful known risk factor predisposing for Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of AIDS-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death if untreated. The mechanisms behind the breakdown of the immune defense of the co-infected individual are not well known. The aim of this review is to highlight immunological events that may accelerate the development of one of the two diseases in the presence of the co-infecting organism. We also review possible animal models for studies of the interaction of the two pathogens, and describe gaps in knowledge and needs for future studies to develop preventive measures against the two diseases.     

Potential of Mycobacterium tuberculosis resuscitation-promoting factors as antigens in novel tuberculosis sub-unit vaccines

Novel vaccines are needed to control tuberculosis (TB), the bacterial infectious disease that together with malaria and HIV is worldwide responsible for high levels of morbidity and mortality. TB can result from the reactivation of an initially controlled latent infection by Mycobacterium tuberculosis (Mtb). Mtb proteins for which a possible role in this reactivation process has been hypothesized are the five homologs of the resuscitation-promoting factor of Micrococcus luteus, namely Mtb Rv0867c (rpfA), Rv1009 (rpfB), Rv1884c (rpfC), Rv2389c (rpfD) and Rv2450c (rpfE). Analysis of the immune recognition of these 5 proteins following Mtb infection or Mycobacterium bovis BCG vaccination of mice showed that Rv1009 (rpfB) and Rv2389c (rpfD) are the most antigenic in the tested models. We therefore selected rpfB and rpfD for testing their vaccine potential as plasmid DNA vaccines. Elevated cellular immune responses and modest but significant protection against intra-tracheal Mtb challenge were induced by immunization with the rpfB encoding DNA vaccine. The results indicate that rpfB is the most promising candidate of the five rpf-like proteins of Mtb in terms of its immunogenicity and protective efficacy and warrants further analysis for inclusion as an antigen in novel TB vaccines.     

结核杆菌潜伏感染小鼠模型的制备及其评价指标

目前对于结核分枝杆菌进入潜伏期的机制以及再激化的原因知之甚少,一个重要的原因是缺乏潜伏感染(LTBI)动物模型,完整的LTBI模型应包括两种类型,一是低剂量荷菌的持续性感染模型,另一种为潜伏感染模型,即Cornell模型的改进型。综合使用柯氏量表评分、脾肺荷菌数、诱导的IFN-γ和TNF-α水平、组织中IL-10和IL-4的表达、脏器中特异性抗原负荷以及激素诱导TB复发的时间、潜伏感染相关基因的表达水平等指标可以比较准确、客观、特异性的评价小鼠LTBI模型的反应性。     

IL-22 Is Mainly Produced by IFNγ-Secreting Cells but Is Dispensable for Host Protection against Mycobacterium tuberculosis Infection

Anti-inflammatory treatment of autoimmune diseases is associated with an increased risk of reactivation tuberculosis (TB). Besides interleukin (IL-17)A, IL-22 represents a classical T helper (TH)17 cytokine and shares similar pathological effects in inflammatory diseases such as psoriasis or arthritis. Whereas IL-17A supports protective immune responses during mycobacterial infections, the role of IL-22 after infection with Mycobacterium tuberculosis (Mtb) is yet poorly characterized. Therefore, we here characterize the cell types producing IL-22 and the protective function of this cytokine during experimental TB in mice. Like IL-17A, IL-22 is expressed early after infection with Mtb in an IL-23-dependent manner. Surprisingly, the majority of IL-22-producing cells are not positive for IL-17A but have rather functional characteristics of interferon-gamma-producing TH1 cells. Although we found minor differences in the number of naive and central memory T cells as well as in the frequency of TH1 and polyfunctional T cells in mice deficient for IL-22, the absence of IL-22 does not affect the outcome of Mtb infection. Our study revealed that although produced by TH1 cells, IL-22 is dispensable for protective immune responses during TB. Therefore, targeting of IL-22 in inflammatory disease may represent a therapeutic approach that does not incur the danger of reactivation TB.     

Not to wake a sleeping giant: new insights into host-pathogen interactions identify new targets for vaccination against latent Mycobacterium tuberculosis infection

Mycobacterium tuberculosis is one of the worlds' most successful and sophisticated pathogens. It is estimated that over 2 billion people today harbour latent M. tuberculosis infection without any clinical symptoms. As most new cases of active tuberculosis (TB) arise from this (growing) number of latently infected individuals, urgent measures to control TB reactivation are required, including post-exposure/therapeutic vaccines. The current bacille Calmette-Guérin (BCG) vaccine and all new generation TB vaccines being developed and tested are essentially designed as prophylactic vaccines. Unfortunately, these vaccines are unlikely to be effective in individuals already latently infected with M. tuberculosis. Here, we argue that detailed analysis of M. tuberculosis genes that are switched on predominantly during latent stage infection may lead to the identification of new antigenic targets for anti-TB strategies. We will describe essential host-pathogen interactions in TB with particular emphasis on TB latency and persistent infection. Subsequently, we will focus on novel groups of late-stage specific genes, encoded amongst others by the M. tuberculosis dormancy (dosR) regulon, and summarise recent studies describing human T-cell recognition of these dormancy antigens in relation to (latent) M. tuberculosis infection. We will discuss the possible relevance of these new classes of antigens for vaccine development against TB.     

TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: A next-generation two-compartmental model

Tuberculosis (TB) is one of the earliest recorded human diseases and still one of the deadliest worldwide. Its causative agent is the bacteria Mycobacterium tuberculosis (Mtb). Cytokine-mediated macrophage activation is a necessary step in control of bacterial growth, and early immunologic events in lymph node and lung are crucial to the outcome of infection, although the factors that influence these environments and the immune response are poorly understood.Our goal is to build the next-generation two-compartmental model of the immune response to provide a gateway to more spatial and mechanistic investigations of M. tuberculosis infection in the LN and lung. Crucial immune factors emerge that affect macrophage populations and inflammation, namely TNF-dependent recruitment and apoptosis, and IL-10 levels. Surprisingly, bacterial load plays a less important role than TNF in increasing the population of infected macrophages and inflammation.Using a mathematical model, it is possible to distinguish the effects of pro-inflammatory (TNF) and anti-inflammatory (IL-10) cytokines on the spectrum of phagocyte populations (macrophages and dendritic cells) in the lung and lymph node. Our results suggest that TNF is a major mediator of recruitment of phagocytes to the lungs. In contrast, IL-10 plays a role in balancing the dominant macrophage phenotype in LN and lung.     

Estimating the burden of tuberculosis among foreign-born persons acquired prior to entering the U.S., 2005-2009

Background

The true burden of reactivation of remote latent tuberculosis infection (reactivation TB) among foreign-born persons with tuberculosis (TB) within the United States is not known. Our study objectives were to estimate the proportion of foreign-born persons with TB due reactivation TB and to describe characteristics of foreign-born persons with reactivation TB.

Methods

We conducted a cross-sectional study of patients with an M. tuberculosis isolate genotyped by the U.S. National TB Genotyping Service, 2005–2009. TB cases were attributed to reactivation TB if they were not a member of a localized cluster of cases. Localized clusters were determined by a spatial scan statistic of cases with isolates with matching TB genotype results. Crude odds ratios and 95% confidence intervals were used to assess relations between reactivation TB and select factors among foreign-born persons.

Main Results

Among the 36,860 cases with genotyping and surveillance data reported, 22,151 (60%) were foreign-born. Among foreign-born persons with TB, 18,540 (83.7%) were attributed to reactivation TB. Reactivation TB among foreign-born persons was associated with increasing age at arrival, incidence of TB in the country of origin, and decreased time in the U.S. at the time of TB diagnosis.

Conclusions

Four out of five TB cases among foreign-born persons can be attributed to reactivation TB and present the largest challenge to TB elimination in the U.S. TB control strategies among foreign-born persons should focus on finding and treating latent tuberculosis infection prior to or shortly after arrival to the United States and on reducing the burden of LTBI through improvements in global TB control.     

A model for tuberculosis with exogenous reinfection

Following primary tuberculosis (TB) infection, only approximately 10% of individuals develop active T.B. Most people are assumed to mount an effective immune response to the initial infection that limits proliferation of the bacilli and leads to long-lasting partial immunity both to further infection and to reactivation of latent bacilli remaining from the original infection. Infected individuals may develop active TB as a consequence of exogenous reinfection, i.e., acquiring a new infection from another infectious individual. Our results in this paper suggest that exogenous reinfection has a drastic effect on the qualitative dynamics of TB. The incorporation of exogenous reinfection into our TB model allows the possibility of a subcritical bifurcation at the critical value of the basic reproductive number R(0)=1, and hence the existence of multiple endemic equilibria for R(0)<1 and the exogenous reinfection rate larger than a threshold. Our results suggest that reducing R(0) to be smaller than one may not be sufficient to eradicate the disease. An additional reduction in reinfection rate may be required. These results may also partially explain the recently observed resurgence of TB.