The Different Outcomes Of A Tuberculosis Infection Biology Essay

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Tuberculosis (TB) is a disease caused by a group of obligate aerobic acid-fast bacilli known as Mycobacterium tuberculosis complex. The group includes Mycobacterium tuberculosis (M.tb), M. bovis, M. africanum and two recently found subspecies (M. canetti and M. microti). M.tb is the main cause of human TB. However, M. bovis and M. africanum can also cause infection to cattle and immuno-compromised individuals. M.tb is an intracellular pathogen and has a predilection for lung tissue that is rich in oxygen supply.

Despite more than 100 years of research, M.tb remains one of the most successful pathogens and TB poses great public health problem(Korbel et al.,2008). According to WHO estimate, there were 9.2 million new cases and 1.7 million deaths in 2007 with high number of mortality and morbidity in Africa, South East Asia, and the pacific countries(WHO,2009). Among the top 15 high TB burden countries, twelve are found in Africa and this high incidence is associated with the relatively high rate of HIV co-infection in the region. Ethiopia is one of the severely affected countries in sub-Saharan Africa. It has an estimated incidence of 378.0 per year in 100,000 populations(WHO,2009).Worldwide, with 11% AIDS related mortality, TB ranks as the leading cause of death in patients with HIV/AIDS(Aaron et al.,2004).

At present, one third of the world population is infected with M.tb. However, 90% of these efficiently control it and do not develop active disease throughout their lifetime. The risk of developing TB increases considerably when the immune system weakens as in the case of HIV infection demonstrating that protective immunity works in the majority of infected individuals to suppress the infection(Korbel et al.,2008). PPD+ HIV+ subjects have 8-10% annual risk of developing active tuberculosis where as PPD+HIV- patients have a 10% lifetime risk (Selwyn et al., 1989 reviewed in Flynn., 2004).

Human Immunodeficiency Virus (HIV) is a retrovirus known to infect CD4+ T lymphocytes, mononuclear phagocytes carrying CD4 molecules on their surfaces and dendritic cells. Then, it results in depletion of CD4 T cells through both direct and indirect mechanisms ultimately resulting in the loss of cell-mediated immunity. When this occurs, the host becomes progressively susceptible to opportunistic infections (OIs)(Daskalakis and Rosenberg,2006).


Mycobacterium tuberculosis infection occurs by aerosol inhalation of droplet of nuclei containing viable, virulent organisms produced by a sputum-positive individual (Fig 1). The bacilli are deposited in the alveolar spaces of the lungs, where they phagocytosed by alveolar macrophages (AM) (Flynn,2004). On entry into a host macrophage, M.tb and other intracellular pathogens initially reside in a phagosome. However, pathogenic mycobacteria escape hostile environment by inhibiting phagosome-lysosome fusion and preventing the acidification of the phagolysosome(Armstrong and Hart,1975). They also also prevent phagosomal maturation and stay in early endosome. Although it is not clear how the blocking of endosomal maturation is essential for M.tb survival in macrophages, it has been postulated that a selective advantage to the bacilli by staying in an early endosome is that there would be less host immunesurveillance by CD4 T cell(Smith,2003).

Figure 1 Different outcome of M.tb infection and underlying mechanisms. Source (Kaufmann and McMichael,2005)

Later, infected macrophages in the lung, through their production of chemokines, attract monocytes, lymphocytes, dendritic cells and neutrophils none of which kill the bacteria efficiently(Fenton and Vermeulen,1996;Van Crevel et al.,2002). Then, granulomatous focal lesions composed of macrophage derived giant cells and lymphocytes begin to form(Schluger and William,1997). This process is generally an effective means of containing the spread of the bacteria. As the cellular immunity develops, macrophages loaded with the bacilli are killed and this results in the formation of the caseous center of the granuloma surrounded by a cellular zone of fibroblasts, lymphocytes, and blood-derived monocytes(Be et al.,2010). Although M.tb bacilli are postulated to be unable to multiply within this caseous tissue due to its acidic pH, the low availability of oxygen, and the presence of toxic fatty acids, some organisms may remain dormant but alive for decades. This enclosed infection is referred to as latent TB and can persist throughout a person's life in an asymptomatic and non transmissible state. The strength of the host cellular immune response determines whether an infection is arrested here or progresses to the next stages(Smith,2003). In persons with efficient cell-mediated immunity, the infection is arrested permanently in granuloma and the granulomas subsequently heal, leaving small fibrous and calcified lesions. In immunecompromised individuals such as HIV patients, however, the ability to confine the bacilli to few infected macrophages will be lost(Nunn et al.,2005). As a result, HIV infected patients have higher risk of developing active TB.


The host's ability to mount an effective immune response is a major determinant of the natural history of TB infection and progress to disease. The immune response to M.tb is primarily cell-mediated and T cells are central to the control of infection (Flynn,2004;Geldmacher et al.,2008). The immunodeficiency resulted from depletion of CD4+ T cells may predispose HIV infected individuals to various bacterial and viral infections (Noursadeghi et al.,2006). As a result, such individuals have higher risk of contracting the so-called "AIDS defining illness" or Opportunistic infections (OIs). Some reports have indicated that HIV positive individuals have a 100-fold increase in pneumococcal bacteraemia and non-typhoidal salmonella species(Aaron et al.,2004). Most OIs cause complications after extended period of HIV infection when CD4 count is less than 200/µl. Few pathogens, however, can cause disease early after HIV seroconversion. One of such pathogen is M.tb. Many studies have indicated that the majority of individuals develop TB with in the first year after HIV infection. In fact, pulmonary TB is the first manifestation of TB in HIV positive individuals in developing countries(Sonnenberg et al.,2005). This suggests that the pathology of M.tb differ from the majority of OIs, which are known to cause complications after host immunity wanes significantly. A study made in South Africa, a TB endemic country, showed that HIV patients with CD4 counts less than 200/μl have a higher risk of developing active TB and most of them experienced TB within a year after HIV seroconversion(Badri et al.,2001;Sonnenberg et al.,2005).

The underlying mechanism for this increased risk of developing TB in HIV patients can be explained partly by immunological defect caused by the virus. Studies have shown that HIV causes immunological dysregulation of both the innate and adaptive immune response. For example, Geldmacher et al. (2008) have shown that TB specific Th1 immune responses are depleted early in HIV infection as seen by low IFN-γ and other Th1 cytokines (TNF-α) production by Peripheral Blood Mononuclear Cells(PBMCs) after stimulated by M.tb specific proteins, Early Secretory Antigenic Target-6 (ESAT-6) and Culture Filtrate Protein-10 (CFP-10) (Geldmacher et al.,2008). HIV can also affect physiological activity of macrophages and, as a result, can cause dysregulation, which otherwise would be sufficient to control the initial spread of the bacilli. This, in fact, necessitates the involvement of Th1 cells and pro inflammatory cytokines to activate macrophages and produce antimycobacterial compounds to effectively kill or/ and tackle the spread of the bacilli. In recent years, many studies have focused on the role of apoptotic death of M.tb infected macrophages and the effect of HIV on this important innate immune mechanism (Patel et al.,2007;Patel et al.,2009;Kumawat et al.,2010). This seminar paper will try to review how HIV causes dysregulation of apoptotic pathway leading to macrophages death and the implication of this to TB immunology.


In multi-cellular organisms, cell death can occur in many contexts-during development, tissue homeostasis, terminal differentiation and disease. In most of these cases, cells are eliminated due to triggering of a process that results in the dismantling of the cell from within(Lockshin and Zakeri,2004). This process, called apoptosis or programmed cell death, is distinctive and different from cell death that occurs during severe cellular insults or necrosis in which injured cell swells, bursts, release its contents and causes maximal inflammatory responses(Rudin and Thompson,1997). However, during apoptosis, a typical cell condense and undergo morphological and biochemical alterations resulting in DNA fragmentation, chromatin condensation and cell shrinkage(Murphy and Martin,2003). The nucleus, cytoplasm and DNA of the cell is degraded into many small pieces forming blebs that are eaten by phagocytic cells before the cellular content have had the chance to escape (Fig 2). This ensures clean and efficient way of removing unwanted or diseased cells while minimizing an inflammatory response resulting from escaping of potentially destructive molecules such as proteases and inflammatory cytokines(Martin,1998;Lockshin and Zakeri,2004). Furthermore, the ability of phagocytes to present peptides from engulfed apoptotic cells may allow the activation of antigen-specific T cells to enhance specific immune responses or regulatory T cells to cause immune deviation or suppression(Rathmell and Thompson,1999).

Figure 2 Schematic representation of apoptosis. Source (Martin,1998)

Apoptosis has been found to be an intrinsic part of all invertebrate and vertebrate multi-cellular animals including nematodes, insects, amphibians and mammals. It plays an essential role in morphogenesis the sculpting of the form of embryos and larvae and in the functional self-organization processes that lead to the maturation of the immune system and the nervous system(Ameisen,1998). It also play an important role in tissue homeostasis, regulation of cell number, elimination of damaged or abnormal cells, and defense against infections. On the other hand, dysregulation of apoptosis whether by extracellular triggers, acquired or germ line genetic mutations, or viral mimicry of signaling molecules lead to several human diseases such as cancer, autoimmunity, AIDS and neurodegenerative disorders(Rudin and Thompson,1997).


The main effectors of apoptosis are intracellular proteases belonging to the caspase family. They are central to initiation and execution of many forms of apoptosis(Lee et al.,2009). In the absence of any activating signal, caspases exist as zymogenes in the cell. Two pathways can trigger their activation and subsequent initiation of apoptotic pathway: extrinsic and intrinsic (Elmore,2007) (Figure 3). The two pathways converge on the same terminal or execution pathway ultimately resulting in the apoptotic death of the cell.

Intrinsic pathway: The Intrinsic pathway (mitochondrial pathway) is a non receptor mediated stimuli initiated in the mitochondria by vast array of stimuli such as nutrient deprivation, oxidative stress, DNA damage, radiation, toxins, hypoxia and viral infection(Elmore,2007;Lee et al.,2009). These stimuli causes in the opening of the mitochondrial permeability transition (MPT) pore and changing of the inner mitochondrial membrane potential, resulting in the loss of trans-membrane potential. At this time, two main groups of pro-apoptotic proteins are released from inner mitochondrial membrane to the cytosol and initiate caspase dependent mitochondrial pathway (Saelens et al., 2004 reviewed in Elmore, 2007). The first group consists of cytochrome c, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis (IAP)-binding protein with low pI (Smac/DIABLO) and serine protease HtrA2/Omi. Cytochrome c binds with the protein Apaf-1 and pro-caspase 9 and triggers the formation of signaling complex called" apoptosome", which then activates caspase-9 by dimerization. Then, active caspase-8 and -9 can proteolytically activate the executioner caspases-3 and 7(Riedl and Scott,2009). Smac/DIABLO and HtrA2/Omi are reported to promote apoptosis by binding with IAP (inhibitors of apoptosis proteins)(Elmore,2007). The second group proteins include Apoptosis Inducing Factor (AIF), endonuclease G and Caspase-Activated DNAse (CAD). Unlike the first group proteins, these pro-apoptotic proteins are released at the late event of apoptosis when the cell is committed to die. For example, AIF move to the nucleus and cause DNA fragmentation and condensation of nuclear chromatin. CAD also translocate to nucleus and cause a more pronounced and advanced form of DNA fragmentation and condensation(Elmore,2007).

The control and regulation of these apoptotic mitochondrial events occurs through members of the Bcl-2 family of proteins that reside in the mitochondria(Bortner and Cidlowski,2002). They govern the membrane permeability by regulating the release of cytochrome c and can be either pro-apoptotic or anti-apoptotic in their activity. Some of the anti-apoptotic proteins include Bcl-2, Bcl-x, Bcl-XL, Bcl-XS, Bcl-w, BAG, and some of the pro-apoptotic proteins include Bcl-10, Bax, Bak, Bid, Bad, Bim, Bik, and Blk(Elmore,2007). These proteins have special significance since they can regulate if the cell commits apoptosis or abort the process.

Figure 3 Schematic representation of extrinsic and intrinsic apoptotic pathway. Source (Elmore,2007)

Extrinsic pathway: The extrinsic (cell surface death receptor) pathway induced after cell surface receptors called" death receptors" are ligated with respective cognate ligands(Lee et al.,2009) (Figure 4). Cell surface death receptors are large members of transmembrane protein belonging to the Tumor Necrosis factor (TNF) super family. Members of the death receptor have a cytoplasmic domain called " death domain" (DD) that can transmit signal from outer cysteine rich extracellular domain to the intracellular signaling pathways(Elmore,2007). Binding of specific ligands to these receptors induces conformational changes that translate to their cytoplasmic tails, leading to the formation of protein complexes referred to as the Death-Inducing Signaling Complex (DISC) that subsequently activate the initiator caspases, particularly caspase 8 and 10(Miura and Koyanagi,2005;Best,2008).

There are many death receptors in mammals such as FasL/FasR, TNF-α/TNFR1, Apo2L/DR4 and Apo2L/DR5. However, the sequence of events leading to extrinsic pathways is well studied with FasL/FasR and TNF-α/TNFR1(Elmore,2007). In FasL/FasR, the binding of trimeric ligands with Fas receptor results in the attachment of the adapter protein Fas-associated death domain (FADD). In TNF-α/TNFR, the binding of TNF ligand to a TNF-α receptors results in the binding of the adapter protein Tumor necrosis factor receptor type 1-associated death domain protein (TRADD) with subsequent recruitment of FADD and Receptor-Interacting Protein (RIP)(Budihardjo et al.,1999). Then, the adapter protein FADD associates with procaspase 8 to trigger the execution pathway(Elmore,2007;Guicciardi and Gores,2009).

Execution Pathway: The final phase of apoptosis in both extrinsic and intrinsic pathways culminates at the execution phase by activating the execution caspases: caspase 3, caspase 6, and caspase 7. These caspases, then, activate the cytoplasmic endonucleases and proteases that can degrade nuclear materials and proteins found in nucleus and cytoplasm respectively. These effector caspases cleave various substrates resulting in morphological and biochemical changes seen in apoptotic cells(Elmore,2007).

Figure 4 Extrinsic or death ligand mediated apoptosis. Source (Miura and Koyanagi,2005)


When phagocytic cells encounter pathogens, a series of event result in internalization, intracellular trafficking and delivery of the pathogen to lysosomes. These events ensure that pathogens taken up by phagocytosis into macrophages are degraded by the combined action of acidic proteases and reactive oxygen and nitrogen species(Sundaramurthy and Pieters,2007). M.tb, however, is an extraordinary pathogen and can survive in hostile host immune response and its success depends on its ability to manipulate eradication by host phagocytic cells especially by macrophages(Porcelli and Jacobs,2008). Many studies have identified the basic strategies by which M.tb modifies normal host cell responses to create a "comfortable milieu" in macrophages. When normal bacteria are internalized by macrophages through phagocytosis, they rapidly destroyed in lysosome(Pieters,2003). M.tb, however, remain in the so called "mycobacterial phagososmes". These compartments normally undergo a process of maturation that includes acidification and fusion with lysosome. M.tb, however, block phagosome maturation, and as a result, the bacilli is able to avoid exposure to bactericidal mechanisms that operate within the lysososme(Sundaramurthy and Pieters,2007).

Figure 5 Cell death of macrophages in apoptosis and necrosis Source (Porcelli and Jacobs,2008)

When M.tb reach an optimal bacillary load and depletes metabolic resources of the host cell, it may induce a cell death to escape from and infect new cells(Briken and Miller,2008). To do this, it acquires the ability to initiate a process that leads to necrotic cell death of host cell. This type of bacterial induced cell death favors the chance of the bacilli from being recognized and attacked by host immune system(Porcelli and Jacobs,2008). In another type of cell death called apoptosis, the host cell is benefited by eradicating the bacilli (Figure 5). The importance of apoptosis in the host's innate immune response was underlined by a report that apoptotic cell death reduced mycobacterial viability, whereas necrotic cell death had no effect on bacterial viability(Molloy et al.,1994).

The importance of apoptosis is also well appreciated in inducing adaptive cell immunity. Macrophages are CD1 negative cells. M.tb infected macrophages also lose their ability to present antigens to CD8 T cells as their phagosomes are secluded from cytosolic MHC-I processing pathway (Schaible et al.,2003). The phagocytosis of apoptotic bodies by CD1 positive dendritic cells lead to the presentation of mycobacterial lipid and peptide antigens and subsequent activation of specific T-cells (Figure 2). This "cross priming" pathway permits an important mechanism by which cytolytic T cells are activated (Schaible et al.,2003;Winau et al.,2004).

Figure 6 Model of the detour pathway: apoptosis facilitate cross-presentation of antigens from intracellular pathogens to CD8 T cells through MHC I and CD1 to enhance antibacterial immunity (Winau et al.,2004)

Even though the importance of apoptosis is well documented in mycobacterial infection, the conclusion reached by different publications is contradictory. Some of these discrepancies can be explained by differences in strains/isolates of mycobacteria used, in the infection procedures and multiplicity of infection, and the nature of the host cell. Gan et al (2008) have shown that macrophages infected with attenuated(H37Ra) M.tb strain become apoptotic while macrophages infected with virulent (H37Rv) strains of M.tb resulted in macrophage death by necrosis(Gan et al.,2008). Study involving clinical isolates using THP-1 cells in India by Rajavelu and Das (2007) showed strain dependent apoptosis of THP-1 cells. In their study, infection of THP-1 cells by a clinical strain called "S7" have shown similar behavior like H37Rv strains of M.tb whereas infection by a clinical strain "S10" showed similarity in apoptosis with H37Ra strains of M.tb (Rajavelu and Das,2007).

The ratio of bacilli to host cell is another factor that determines the outcome of host cell death. In their study, Lee and his colleagues used different MOI to determine apoptosis of murine macrophages and their result showed that high MOI (>25) using H37Rv induce much elevated apoptosis than H37Ra strains of M.tb. In the same study, infection with BCG has also shown similar result. This type of cell death have been shown to promote bacterial viability and extracellular spread of infection(Lee et al.,2006). The same result has been also observed when macrophages infected at low MOI cultured for several days to permit the replication of the bacilli above the threshold level.


The induction of apoptosis following infection of apoptosis is an old defense mechanism observed in many organisms ranging from Caenorhabditis elegans (C.elegans) to humans. It is therefore not surprising to see the evolution of mechanisms by viral, bacterial and protozoan to actively inhibit this self-suicidal mechanism(Elmore,2007). Many intracellular bacterial pathogens have evolved anti apoptotic mechanisms to avoid host the response and continue replication(Weinrauch and Zychlinsky, 1999).The importance of apoptosis by M.tb can be seen by evolution of anti apoptotic gene and interfering with mechanisms that lead to apoptosis including modification of death receptors such as Fas (CD95) and the soluble TNF receptor 2 (sTNFR2). Many studies have shown that M.tb differentially regulate the apoptosis of macrophages by modifying the pro- and anti-apoptotic proteins (Sly et al.,2003).

The expression of the anti apoptotic protein, mcl, was found to be high when Monocytes Derived Macrophages (MDM) and THP-1 cells are infected with H37Rv (Sly et al.,2003). Analysis of mMcl-1 mRNA in THP-1 cells by infecting with attenuated M.tb strain H37Ra, heat-killed H37Rv, latex beads or live H37Rv in the same study shows that none of them induces mRNA of mcl except live H37Rv(Sly et al.,2003).

A study made by Balcewicz-Sablinska et al.(1998) showed that virulent M.tb(H37Rv) inactivate the pro-apoptotic cytokine, TNF-α, in IL-10 dependent manner in alveolar macrophages by releasing of soluble TNFR2 (sTNFR2). By forming complex with TNF-α, sTNFR2 abrogates the induction of apoptosis upstream of the death-signaling cascade by elimination of the inducing cytokine signal (Balcewicz-Sablinska et al.,1998).

Another mechanism by which M.tb abrogates apoptosis is the reduction of Fas expression on infected macrophages and reduced susceptibility to Fas L apoptosis by CD4+ T cells(Oddo et al.,1998). This reduces the susceptibility of M.tb infected macrophages to FasL-induced apoptosis and increase the intracellular growth of the bacilli.


Monocyte-macrophages (M/M) express the CD4 molecule on their surface and can be infected with HIV both in vitro and in vivo. Several studies have shown that M/M play an important role in the pathogenesis of HIV infection. They act as a reservoir and can transmit the virus to autologus CD4 T cells(Mahlknecht and Herbein,2001). They can also induce apoptosis of T cells resulting in rapid cell death and decline of CD4 T cells (Badley et al.,1997).

Comparison of CD4 T cells and M/M after short-term infection (14 days) by HIV has shown rapid increase in viral RNA followed by massive cell death in the previous cells than the later (Aquaro et al.,2002). The same study showed that viral replication in M/M does not reach its plateau with in this short time. In fact, it took very long time (60 days) to reach at plateau of viral RNA in infected M/M. Survival of infected M/M for several weeks with continual production of virion suggest that these cells act as reservoir of the virus. Their capacity to migrate in organs and to survive in tissue makes them also potential conveyors of the virus(Verani et al.,2005). Study by Crowe et al. (1990) showed that HIV infected macrophages could successfully transmit the virus to CD4 expressing cells (Crowe et al.,1990). Infected macrophages also secret two type of chemokines- Macrophage Inflammatory Protein(MIP)1α and MIP1β, which can recruit and activate resting CD4 T cells; CD4 cells recruited in this way, then, become infected and produce viral particles before they die (Liou et al.,2004). This observation was corroborated by Groot et al. (2008) who found that HIV infected macrophages can infect at least one T cell every six hour(Groot et al.,2008). Since HIV-1-infected, macrophages can survive for many weeks, this slow turnover of infected M/M play an important role in virus spreading and disease progression(Crowe et al.,2003;Swingler et al.,2007).

The role of HIV infected macrophages in the induction of apoptosis of CD4 T cells was described by a study made in Severe Combined Immuno-Deficient(SCID) mice(Mosier et al.,1993). In their study, Mosier et al. (1993) transplanted human peripheral blood leuckocyte to SCID mice and infected them with HIV isolates that have different cytopathicity. The two M-tropic isolates - HIV-1SF162 and HIV-2UC1- induced extensive CD4 cell depletion while the HIV-1SF33 which is highly cytopathic in vitro for T cells showed little CD4 depletion. This and other observations suggested that M/Ms might play a crucial role in CD4T-cell depletion upon HIV infection and the virus might use mechanisms to abrogate apoptotic cell death of M/M to sustain its persistence and increase its replication(Mahlknecht and Herbein,2001).


Both CD4 and M/M are targets of HIV infection and support viral replication. To maintain its niche and continue replication, HIV encodes several genes (tat, nef etc) that have been reported to have both anti-apoptotic and pro-apoptotic functions(Chen et al.,2004). Indeed, the virus likely employs both anti- and pro-apoptotic mechanisms to preserve the latently infected cell (e.g. M/M) and facilitate transmission. At the same time, the virus contributes to the death of CD4+T lymphocytes characteristic of the later stages of disease and loss of immune competence in patients through both direct and bystander mechanism of apoptosis induction(Yang et al.,2003). Therefore, both inhibition and/or enhancement of apoptosis can contribute to HIV pathogenesis (Guillemard et al.,2004).


Alteration of TNF mediated apoptosis

TNF-α is pleiotrophic cytokine mainly produced by macrophages. It elicits both pro-apoptotic and anti-apoptotic activity through induction of the caspase cascade and NF-ĸB respectively. By binding with TNFR1 that has a death domain in the intracytoplasmic portion, this cytokine promotes death signal by recruiting adapter protein TRADD and FADD, which subsequently lead to caspase 8 activation (Figure 7). This, then, follows with initiation of execution pathway by activating caspase 3 which ultimately resulting in the loss of mitochondrial trans-membrane potential. This also accompanied by the release of smac/DIABLO from the mitochondria that can inhibit the activities of IAP that suppresses the activities of caspase 3(Liu et al.,2004).

Figure 7 TNF-induced receptor trimerizations aggregates the death domains (DD) of tumor necrosis factor TNFR1 and recruits the adaptor protein TRADD and FADD and initiate apoptosis. The adaptor protein TRADD can also recruit TRAF2, which subsequently activate NF-ĸB that has anti-apoptotic factors. Source(Dash,2010).

To inhibit TNF associated death pathway, HIV alters the differential expression of Toll Like Receptor (TLR). TLR are members of receptors on the surface of phagocytes and other cells that signal macrophage activation following recognition of microbial products such as endotoxins(Uematsu and Akira,2008). To date 13 TLRs have been described, which can recognize various pathogen-associated molecular patterns (PAMPS). TLR 1, 2 and 6 recognize PAMPs that are associated with gram-positive bacteria, fungi, and mycobacteria whereas TLR 4 act as receptor for gram negative bacterial lipopolysaccharide (LPS)(Uematsu and Akira,2008). This receptor mediated interaction triggers downstream signaling cascades ultimately resulting in the up regulation of early markers of inflammatory responses. One of the TLR induced cytokines in the lungs is TNF-α. A study made by Nicol et al. (2008) have shown a decreased in both surface expression of TLR 1, 2 and 4 and in gene expression of TNF from HIV infected monocytic cell lines(Nicol et al.,2008). The production of TNF in response to TLR-2 and TLR-4 ligands has also been found to be lower in AM from HIV infected individuals.

Another study by Tachado et al. (2008) in AM and monocytic cell line U937 have shown similar expression of TLR4 expression in both HIV infected and uninfected cells (Tachado et al.,2008). However, TLR4 activation of HIV infected cells resulted in low production of TNF (Tachado et al.,2008). Recognition of the viral protein Nef by TLR4 can activate Phosphoinositide 3-kinases (PI3K) which, in turn, activates Protein Kinase B (Akt), a key effector of PI3K pathway(Kumawat et al.,2010). Activated Akt, then, phosphorylates glycogen synthase kinase-3β (GSK-3β) resulting in GSK-3β inactivation and dampening of pro inflammatory immune response. This suppression, mediated by the anti-inflammatory cytokine Interleukin 10 (IL-10) and Transforming Growth Factor β (TGF-β), result in the inhibition of TLR mediated TNF-α release (Tachado et al.,2008). Using HIV infected THP-1 cells as a model of infection, Pathak et al. have also found reduced secretion of TNF-α and a suppressed IL-1 receptor associated kinase 4 (IRAK-4), which is essential for all TLR signaling(Pathak et al.,2009). Another study by Patel et al. (2009) have shown an increased production of IL-10 and this anti-inflammatory cytokine decrease mRNA level of TNF-α and increase the levels of alveolar macrophages (AM) B Cell Lymphoma-3 (BCL-3). BCL-3 is an inhibitory protein of IkB proteins that can bind with NF-kB and render the transcriptional factor inactive in the cytoplasm (Patel et al.,2009). This would suppress TNF mRNA and protein production by inhibiting the nuclear translocation of the NF-kB.

Alteration of TRAIL mediated apoptosis

Another mechanism by which HIV sustains the survival of macrophages is through the regulation of death receptor mediated apoptosis induced by Tumor necrosis factor-Related Apoptosis Inducing Signal (TRAIL) (Swingler et al.,2007). TRAIL, also known as Apo-2L, is an apoptosis inducing member of TNF family that can induce apoptosis when binding to its receptor that bear an intracellular death domain (Pitti et al.,1996). It can exist as both membrane bound and soluble form. It binds with different receptors including TRAIL-1/Death receptor (DR)-4, TRAIL-R2/DR-5, TRAIL-R3, TRAIL-R4 and osteoprotegerin. When TRAIL bind to the first two receptor which contain death domain, it can initiate caspase 8, and this further activate the effector caspases 3, 6 and 7 to mediate apoptosis.

TRAIL mediated apoptosis of macrophages can be induced by CD4 T, CD8 and NK cells to maintain homeostasis of Antigen Presenting Cells (APCs) (Kaplan et al.,2000). It is also one mechanism used by host cell to eradicate intracellular pathogens(Richardson et al.,1993). In addition, experiments have shown that neutralization of TRAIL but not Fas ligand on T cells prevented apoptosis of HIV infected macrophages demonstrating that TRAIL mediated apoptosis may play a main role in apoptotic death of macrophages. Therefore, the avoidance of apoptosis by TRAIL is likely an important mechanism for survival of HIV infected macrophages in vivo. Indeed, Swingler et al. (2007) have shown that the HIV glycoprotein causes blocking of TRAIL mediated apoptosis in Monocyte-Colony Stimulating Factor (M-CSF) dependent manner(Swingler et al.,2007). This pro-survival cytokine causes the down regulation of the TRAIL receptor (TRAIL-R1/DR4) and up regulate the anti apoptosis genes Bfl-1 and Mcl-1. The importance of M-CSF is revealed by neutralization experiment using an antibody against this cytokine in which apoptosis sensitivity were restored.


Modulation of the intrinsic pathway is another mechanism HIV uses to induce resistance to apoptotic death of macrophages (Fernandez Larrosa et al.,2008). One way to attain this is through modulation of the Bcl-2 family proteins. In fact, Giri and his colleagues reported that monocytes infected with HIV do show steady state anti apoptotic gene signature composed of 38 genes (Giri et al.,2009). The modulation of the Bcl-2 proteins is a well known mechanism used by the virus to induce/prevent apoptosis of CD4 and CD8 T cells by up regulating or/and down regulating pro- and anti-apoptotic proteins(de Oliveira Pinto et al.,2002;Petrovas et al.,2004).

Several in vitro and in vivo studies have shown that HIV regulates apoptotic death of Mø to increase its survival in these relatively long-lived cells. A study made by Guillemard et al. (2004) showed that HIV increased the production of the anti-apoptotic protein, Bcl-2 and Bcl-XL in TNF dependent manner by activating NF-ĸB (Guillemard et al.,2004)(Figure 7). Several HIV proteins have been implicated for this resistance to apoptosis of monocytes. For example, the HIV Tat protein was found to increase the expression of Bcl-2 when incubated with monocytes and such cells showed less sensitivity to TRAIL mediated apoptosis (Zheng et al.,2007). It is believed that the main effect of the anti-apoptotic Bcl-2 targeted the mitochondrial membrane although direct effects on caspase activity have been reported.


In the present era, HIV-TB co infection possesses great problem to the management of the two diseases. Studies have shown that HIV exacerbates the progression of TB through several mechanisms. Although HIV-1 infection does not typically cause depletion of M/M, it causes significant defect in the intrinsic macrophage mediated defense against variety of intracellular pathogens(Lawn et al.,2002). One way to do this is through attenuation of apoptosis death of macrophages. Apoptosis of macrophages in response to M.tb represents a critical host defense response, and a decrease in apoptosis represents one mechanism of increased vulnerability to M.tb in HIV infected patients (Patel et al.,2007). In recent time, many studies have concentrated to depict the mechanisms on how HIV affects the apoptotic cell death of M.tb infected Macrophages. Reduced TNF-α mediated response associated with increased anti-inflammatory cytokines such as IL-10 and TGF-β and the up regulation of BCL-3 and increased TNF scavenging by sTNFR2 may account for attenuation of apoptotic death of M.tb and subsequent high TB incidence in HIV infected individuals. Recognition of these and other intrinsic defects resulted from HIV infection leading to apoptotic death of M/M may represent a potential therapeutic target or prevention of TB in HIV-infected individuals.