Editorial: Live or let die—does HIV exacerbate tuberculosis by attenuating M. tuberculosis-induced apoptosis?

Abstract

TB remains the leading cause of bacterial-mediated mortality with 9.2 million new cases of TB reported in 2006 [1]. The susceptibility of HIV individuals to TB has fueled the spread of tuberculous disease, and HIV is the single most powerful risk factor for the development of TB [1]. As such, dissecting the factors that promote susceptibility to TB in HIV individuals is an urgent priority. HIV individuals exhibit increased susceptibility to tuberculous disease even with relatively preserved CD4 T lymphocyte counts [2, 3], and this risk remains high after effective anti-retroviral therapy and immune reconstitution [4, 5]. This is suggestive of an early and persistent defect in immunity to Mtb, which is independent of the overall total CD4 T lymphocyte count. The nature of this defect is unknown but may reside in the Mtbspecific adaptive immune response, where it could be a result of quantitative or qualitative differences in T cell responses or alternatively, in the innate immune response. The primary niche of the tubercule bacillus, the macrophage, is a key component of the innate immune response to Mtb. Within this hostile environment, Mtb manages to survive and replicate where most other pathogens perish. However, the balance between the host and pathogen in this interaction is complex and the bacilli’s home can become its final resting place if the balance is tipped in the macrophage’s favor, as is observed in the contrasting effects of the host cell death mechanisms apoptosis and necrosis. Although necrosis of the infected macrophage does not alter the viability of the intracellular mycobacteria and allows bacillary egress from cell to cell, resulting in disease progression [6], during host cell apoptosis, the intracellular environment swiftly becomes hostile. Indeed, macrophage apoptosis represents a key innate immune strategy used by the host, which results in loss of viability of the intracellular mycobacteria [7–9] by apoptotic-associated effector functions or by uptake of the apoptotic body by an incoming macrophage. In addition, the uptake of apoptotic vesicles by uninfected bystander antigen presenting cells facilitates antigen presentation to MHC Class I and CD1-restricted T lymphocytes, thus enhancing acquired immunity to Mtb [10]. However, Mtb has evolved mechanisms of down-regulating macrophage apoptosis, and virulent Mtb is able to manipulate the host apoptotic pathway by specifically up-regulating the antiapoptotic bcl-2 family members mcl-1, A1, and Bcl-W [9, 11–13] and by inhibiting completion of the apoptotic envelope [14] and hence, shifting the balance in its favor. In vivo, HIV infects macrophages as well as T cells, and HIV infection of monocyte-derived macrophages has been reported to increase the growth of intracellular Mtb [15]. HIV also infects AM in a persistent manner [16], and it was noted that Mtb-specific TNFrelease and TNF-mediated apoptosis were reduced in AM from asymptomatic HIV individuals when compared with healthy individuals and in HIV-infected AM from healthy individuals (n 3 of each) [17]. The reduction of Mtb-induced, TNF-mediated apoptosis in this manner may enhance the susceptibility of HIV patients to TB. The paper by Patel et al. [18], published in the current issue of the journal, elegantly defines a molecular mechanism by which HIV impairs the host anti-mycobacterial apoptotic response. The authors report again that in asymptomatic HIV individuals, compared with healthy controls, TNF-mediated, Mtb-induced apoptosis is decreased in AM (n 4 in each group here) and also shows that IL-10 is increased in BAL from asymptomatic HIV individuals (n 25 HIV ; n 15 healthy controls). IL-10 has been reported previously to