The dual burden of tuberculosis (TB) and diabetes has attracted much attention in the past decade as diabetes prevalence has increased dramatically in countries already afflicted with a high burden of TB. The confluence of these two major diseases presents a serious threat to global public health; at the same time it also presents an opportunity to learn more about the key elements of human immunity to TB that may be relevant to the general population. Some effects of diabetes on innate and adaptive immunity that are potentially relevant to TB defense have been identified, but have yet to be verified in humans and are unlikely to fully explain the interaction of these two disease states. This review provides an update on the clinical and epidemiological features of TB in the diabetic population and relates them to recent advances in understanding the mechanistic basis of TB susceptibility and other complications of diabetes. Issues that merit further investigation — such as geographic host and pathogen differences in the diabetes/TB interaction, the role of hyperglycemia‐induced epigenetic reprogramming in immune dysfunction, and the impact of diabetes on lung injury and fibrosis caused by TB — are highlighted in this review.

Lymphocyte chemoattractant factor (LCF) is a lymphocyte cell product that stimulates a migratory response in CD4+ lymphocytes, monocytes, and eosinophils. In concert with its chemoattractant activity, LCF induces human T-lymphocyte expression of interleukin 2 receptor. Here we describe the molecular cloning of cDNA encoding human LCF. It is a novel interleukin with no significant homology to any previously described cytokine families. There is an absolute requirement for both autoaggregation of LCF monomers and for membrane-expressed CD4 molecules for LCF-induced migration in lymphocytes.

We previously reported thatMycobacterium tuberculosisinfection primes human alveolar macrophages (HAM) for tumor necrosis factor alpha (TNF-α)-mediated apoptosis and that macrophage apoptosis is associated with killing internalized bacilli. Virulent mycobacterial strains elicit much less apoptosis than attenuated strains, implying that apoptosis is a defense against intracellular infection. The present study evaluated the potential for phorbol myristate acetate-differentiated THP-1 cells to mimic this response of primary macrophages. Consistent with the behavior of alveolar macrophages, attenuatedM. tuberculosisH37Ra andMycobacterium bovisBCG strongly induce THP-1 apoptosis, which requires endogenous TNF. THP-1 apoptosis is associated with reduced viability of infecting BCG. In contrast, virulent wild-typeM. tuberculosisH37Rv andM. bovisdo not increase THP-1 apoptosis over baseline. BCG induced early activation of caspase 10 and 9, followed by caspase 3. In contrast, wild-typeM. bovisinfection failed to activate any caspases in THP-1 cells. BCG-induced THP-1 apoptosis is blocked by retroviral transduction with vectors expressingcrmAbut notbcl-2. We conclude that differentiated THP-1 cells faithfully model the apoptosis response of HAM. Analysis of the THP-1 cell response to infection with virulent mycobacteria suggests that TNF death signals are blocked proximal to initiator caspase activation, at the level of TNF receptor 1 or its associated intracytoplasmic adaptor complex. Interference with TNF death signaling may be a virulence mechanism that allowsM. tuberculosisto circumvent innate defenses leading to apoptosis of infected host cells.

Increased susceptibility to infections, including tuberculosis (TB), is a major cause of morbidity and mortality in patients with diabetes. Despite the clinical importance of this problem, little is known about how diabetes impairs protective immunity. We modeled this phenomenon by infecting acute (≤ 1 mo) or chronic (≥ 3 mo) diabetic mice with a low aerosol dose of Mycobacterium tuberculosis (Mtb) Erdman. Diabetes was induced by streptozotocin (STZ) treatment of C57BL/6 mice, while another mouse strain and diabetes model were used to confirm key observations. Lungs from acute diabetic and euglycemic mice had similar bacterial burdens, cytokine expression profiles, and histopathology. In contrast, chronic diabetic mice had > 1 log higher bacterial burden and more inflammation in the lung compared with euglycemic mice. The expression of adaptive immunity was delayed in chronic diabetic mice, shown by reduced early production of IFN-γ in the lung and by the presence of fewer Mtb antigen (ESAT-6)–responsive T cells compared with euglycemic mice within the first month of infection. However, after 2 months of TB disease proinflammatory cytokines levels were higher in chronic diabetic than euglycemic mice. Here we show that Mtb infection of STZ-treated mice provides a useful model to study the effects of hyperglycemia on immunity. Our data indicate that the initiation of adaptive immunity is impaired by chronic hyperglycemia, resulting in a higher steady-state burden of Mtb in the lung.

Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB) but the defect in protective immunity responsible for this has not been defined. We previously reported that streptozotocin-induced DM impaired TB defense in mice, resulting in higher pulmonary bacterial burden, more extensive inflammation, and higher expression of several proinflammatory cytokines known to play a protective role in TB. In the current study, we tested the hypothesis that DM leads to delayed priming of adaptive immunity in the lung-draining lymph nodes (LNs) following low dose aerosol challenge with virulent Mycobacterium tuberculosis. We show that M. tuberculosis-specific IFN-γ–producing T cells arise later in the LNs of diabetic mice than controls, with a proportionate delay in recruitment of these cells to the lung and stimulation of IFN-γ–dependent responses. Dissemination of M. tuberculosis from lung to LNs was also delayed in diabetic mice, although they showed no defect in dendritic cell trafficking from lung to LNs after LPS stimulation. Lung leukocyte aggregates at the initial sites of M. tuberculosis infection developed later in diabetic than in nondiabetic mice, possibly related to reduced levels of leukocyte chemoattractant factors including CCL2 and CCL5 at early time points postinfection. We conclude that TB increased susceptibility in DM results from a delayed innate immune response to the presence of M. tuberculosis-infected alveolar macrophages. This in turn causes late delivery of Ag-bearing APC to the lung draining LNs and delayed priming of the adaptive immune response that is necessary to restrict M. tuberculosis replication.

We previously reported that Mycobacterium tuberculosis triggers macrophage necrosis in vitro at a threshold intracellular load of ∼25 bacilli. This suggests a model for tuberculosis where bacilli invading lung macrophages at low multiplicity of infection proliferate to burst size and spread to naïve phagocytes for repeated cycles of replication and cytolysis. The current study evaluated that model in vivo, an environment significantly more complex than in vitro culture. In the lungs of mice infected with M. tuberculosis by aerosol we observed three distinct mononuclear leukocyte populations (CD11b⁻ CD11c^+/hi, CD11b^+/lo CD11c^lo/−, CD11b^+/hi CD11c^+/hi) and neutrophils hosting bacilli. Four weeks after aerosol challenge, CD11b^+/hi CD11c^+/hi mononuclear cells and neutrophils were the predominant hosts for M. tuberculosis while CD11b^+/lo CD11c^lo/− cells assumed that role by ten weeks. Alveolar macrophages (CD11b⁻ CD11c^+/hi) were a minority infected cell type at both time points. The burst size model predicts that individual lung phagocytes would harbor a range of bacillary loads with most containing few bacilli, a smaller proportion containing many bacilli, and few or none exceeding a burst size load. Bacterial load per cell was enumerated in lung monocytic cells and neutrophils at time points after aerosol challenge of wild type and interferon-γ null mice. The resulting data fulfilled those predictions, suggesting a median in vivo burst size in the range of 20 to 40 bacilli for monocytic cells. Most heavily burdened monocytic cells were nonviable, with morphological features similar to those observed after high multiplicity challenge in vitro: nuclear condensation without fragmentation and disintegration of cell membranes without apoptotic vesicle formation. Neutrophils had a narrow range and lower peak bacillary burden than monocytic cells and some exhibited cell death with release of extracellular neutrophil traps. Our studies suggest that burst size cytolysis is a major cause of infection-induced mononuclear cell death in tuberculosis. Macrophages patrol the lung to ingest and destroy inhaled microbes. Mycobacterium tuberculosis, the bacteria causing tuberculosis, can survive within macrophages and use them as a protected environment for growth. Macrophages by themselves are poorly equipped to kill M. tuberculosis but may undergo programmed cell death (apoptosis) to limit bacterial replication. Virulent M. tuberculosis has evolved the capacity to inhibit macrophage apoptosis, thereby protecting the replication niche. In previous studies we showed that upon reaching a threshold intracellular number (burst size), virulent M. tuberculosis kills macrophages by necrosis and escapes for spreading infection. The present study was designed to test whether this mechanism seen in vitro operates during pulmonary tuberculosis in vivo. The distribution of M. tuberculosis numbers inside lung phagocytes of mice with tuberculosis conformed to predictions based on the burst size hypothesis, as did the appearance of dying cells. We identified four different types of phagocytes hosting intracellular M. tuberculosis. The distribution of M. tuberculosis load within individual phagocytes and between different types of phagocyte changed over the course of tuberculosis disease. These studies reveal the complexity of host defense in tuberculosis that must be considered as new therapies are sought.