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The role of the innate immune response and host resistance to Mycobacterium tuberculosisinfection (TB) is reviewed. Based on our data and the abundant literature, an early type 1 immune response is critical for infection control, while ILC3 and Th17 cells seem to be dispensable. Indeed, in M. tuberculosisinfected mice, transcriptomic levels of Il17, Il17ra, Il22and Il23awere not significantly modified as compared to controls, suggesting a limited role of IL-17 and IL-22 pathways in TB infection control. Neutralization of IL-17A or IL-17F did not affect infection control either. Ongoing clinical studies with IL-17 neutralizing antibodies show high efficacy in patients with psoriasis without increased incidence of TB infection or reactivation. Therefore, both experimental studies in mice and clinical trials in human patients suggest no risk of TB infection or reactivation by therapeutic IL-17 antibodies, unlike by TNF.

Mine dust has been linked to the development of pneumoconiotic diseases such as silicosis and coal workers’ pneumoconiosis. Currently, it is understood that the physicochemical and mineralogical characteristics drive the toxic nature of dust particles; however, it remains unclear which parameter(s) account for the differential toxicity of coal dust. This study aims to address this issue by demonstrating the use of the partial least squares regression (PLSR) machine learning approach to compare the influence of D50sub 10 μm coal particle characteristics against markers of cellular damage. The resulting analysis of 72 particle characteristics against cytotoxicity and lipid peroxidation reflects the power of PLSR as a tool to elucidate complex particle-cell relationships. By comparing the relative influence of each characteristic within the model, the results reflect that physical characteristics such as shape and particle roughness may have a greater impact on cytotoxicity and lipid peroxidation than composition-based parameters. These results present the first multivariate assessment of a broad-spectrum data set of coal dust characteristics using latent structures to assess the relative influence of particle characteristics on cellular damage.

ABSTRACTMycobacterium tuberculosisinfection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions of M. tuberculosiswith neurons in vitroand in vivowere investigated. The data obtained demonstrate that neurons can act as host cells for M. tuberculosis. M. tuberculosisbacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization of M. tuberculosisbacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalize M. tuberculosis. Internalized M. tuberculosisbacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h. M. tuberculosisbacillus infection of neurons was confirmed in vivoin the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells for M. tuberculosiswithin the central nervous system.

ABSTRACTThe contraceptive depot medroxyprogesterone acetate (DMPA), with progestin as the single active compound, possesses selective glucocorticoid activity and can alter the expression of glucocorticoid receptor-regulated genes. We therefore propose that pharmacological doses of DMPA used for endocrine therapy could have significant immune modulatory effects and impact on susceptibility to, as well as clinical manifestation and outcome of, infectious diseases. We investigated the effect of contraceptive doses of DMPA in two different murine Mycobacterium tuberculosismodels. Multiplex bead array analysis revealed that DMPA altered serum cytokine levels of tumor necrosis factor alpha (TNF-a), granulocyte colony-stimulating factor (G-CSF), and interleukin 10 (IL-10) in C57BL/6 mice and gamma interferon (IFN-?) in BALB/c mice. DMPA also suppressed antigen-specific production of TNF-a, G-CSF, IL-10, and IL-6 and induced the production of IP-10 in C57BL/6 mice. In BALB/c mice, DMPA altered the antigen-specific secretion of IFN-?, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and monocyte chemotactic protein 1 (MCP-1). Furthermore, we show that C57BL/6 mice treated with doses of DMPA, which result in serum concentrations similar to those observed in contraceptive users, have a significantly higher bacterial load in their lungs. Our data show for the first time that DMPA impacts tuberculosis (TB) disease severity in a mouse model and that the effects of this contraceptive are not confined to infections of the genital tract. This could have major implications for the contraceptive policies not only in developing countries like South Africa but also worldwide.

Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium bergheiANKA (PbA)–induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-θ) in experimental CM development was examined. PKC-θ–deficient mice are resistant to CM development. In the absence of PKC-θ, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC-θ–deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8+T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-θ. Resistant PKC-θ–deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-θ signaling is crucial for recruitment of CD8+T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.

AbstractThe interactions between Mycobacterium tuberculosisand host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many receptors have been implicated in recognition and binding of M. tuberculosissuch as the mannose receptor, dendritic-cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, dectin-1 and complement receptor 3 as well as Toll-like receptors, scavenger receptors and CD14. While in vitro studies have demonstrated clear roles for particular recep- tor(s), in vivo work in receptor-deficient animals often revealed only a minor, or no role, in infection with M. tuberculosis. The initial encounter of phagocytic cells with myco- bacteria appears to be complex and depends on various parameters. It seems likely that infection with M. tuberculosisdoes not occur via a single receptor-mediated pathway. Rather, multiple receptors play different roles in M. tuberculosisinfection, and the overall effect depends on the expression and availability of a particular receptor on a particular cell type and its triggered downstream responses. Moreover, the role of membrane cholesterol for M. tuberculosisinteractions with phagocytes adds to the complexity of mycobacterial recognition and response. This review summarizes current knowledge on non-opsonic receptors involved in binding of mycobacteria and discusses the contribution of individual receptors to the recognition process.Copyright © 2008 S. Karger AG, Basel

ABSTRACTWe compared the growth levels and pathogenicities of the Mycobacterium tuberculosisMT103 clinical strain with those of the ΔpurCmutant strain MYC1551, which is auxotrophic for purine in wild-type and gamma interferon receptor (IFN-γR)-deficient mice. The ΔpurCstrain MYC1551 grew initially in both wild-type and IFN-γR-deficient mice upon aerosol infection, but it grew much less than strain MT103 did. Despite the comparable bacterial burdens of the mice, IFN-γR-deficient mice succumbed to infection with ΔpurCstrain MYC1551 from necrotic pneumonia within 6 weeks of those infected with MT103. In conclusion, the ΔpurCmutant MYC1551 displays reduced growth but retains pathogenicity. Therefore, the use of mutant strains of M. tuberculosisas live vaccines may not be recommended.

Recognition of Mycobacterium tuberculosisby the innate immune system is essential in the development of an adaptive immune response. Mycobacterial cell wall components activate macrophages through Toll-like receptor (TLR) 2, suggesting that this innate immune receptor plays a role in the host response to M. tuberculosisinfection. After aerosol infection with either 100 or 500 live mycobacteria, TLR2-deficient mice display reduced bacterial clearance, a defective granulomatous response, and develop chronic pneumonia. Analysis of pulmonary immune responses in TLR2-deficient mice after 500 mycobacterial aerosol challenge showed increased levels of interferon-γ, tumor necrosis factor-α, and interleukin-12p40 as well as increased numbers of CD4+and CD8+cells. Furthermore, TLR2-deficient mice mounted elevated Ag-specific type 1 T-cell responses that were not protective because all deficient mice succumb to infection within 5 months. Taken together, the data suggests that TLR2 may function as a regulator of inflammation, and in its absence an exaggerated immune inflammatory response develops.

AbstractThe role of the endogenous interleukin-10 (IL-10) in the control of Mycobacterium bovisBacille Calmette Guerin (BCG) infection was assessed using IL-10-deficient (IL-10-/-)mice. Similar to wild-type (WT) mice, IL-10-/-mice were resistant to intravenous challenge with Mycobacterium bovisBCG. Significantly higher plasma concentrations of IL-12 and tumour necrosis factor (TNF) indicated an elevated protective immune response of IL-10-/-mice. Determination of bacilli burden in IL-10-/-mice showed accelerated clearance in the lungs, spleen and the liver in comparison to WT mice. Enhanced inflammation and a vigorous granulomatous response accompanied accelerated mycobacterial clearance. Immunohistochemical analysis of hepatic granulomas from IL-10-/-mice revealed augmented lymphocyte recruitment and macrophage activation, such as increased major histocompatibility complex (MHC) class II and inducible nitric oxide synthase (iNOS) expression. Further, it was found that enlarged granulomas persisted subsequent to mycobacterial clearance and failed to resolve in the absence of IL-10. In conclusion, endogenous IL-10 dampens the cell-mediated immune response to mycobacterial infection.

Neutralization of TNF or disruption of TNF-R1 leads to fatal Mycobacterium bovisBCG infection. Here we used TNF-LT-α-deficient mice to test whether a complete disruption of TNF and LT-α reduces further host resistance to BCG infection. The bacterial burden especially in the lungs of TNF-LT-α-deficient mice was significantly increased and the mice succumbed to infection between 8 and 10 weeks. In the absence of TNF-LT-α the granulomatous response was severely impaired and delayed. The cells in the granulomas of TNF-LT-α-deficient mice expressed low levels of MHC class II and ICAM-1. They contained a few T cells and F4/80-positive macrophages expressing little iNOS and acid phosphatase activity. By contrast, the lethal action of endotoxin was dramatically reduced in BCG-infected TNF-LT-α-deficient mice. In summary, in the absence of TNF-LT-α the recruitment and activation of mononuclear cells in response to BCG infection were significantly delayed and reduced resulting in immature granulomas allowing uncontrolled fatal infection.