Immunity Against Bacterial Infection of the Central Nervous System: An Astrocyte Perspective

Bacterial infection of the central nervous system (CNS) is a severe and life-threatening condition with high mortality, and it may lead to permanent neurological deficits in survivors. Increasing evidence indicates that astrocytes, as the most abundant CNS glial cell population, regulate innate and adaptive immune responses in the CNS under pathological conditions in addition to their role in the maintenance of CNS homeostasis and neuronal function. Following antigen recognition, astrocytes participate in the initiation of innate immune responses, and prompt an adaptive immune response to recruit peripheral immune cells. Investigations have been conducted to understand the immunological role of astrocytes in CNS disease and injury, however, their part in bacterial infections of the CNS has not been fully evaluated. A better understanding will permit the identification of successful therapeutic targets for an improved prognosis and disease outcome

Immunity to the Dual Threat of Silica Exposure and Mycobacterium tuberculosis

Exposure to silica and the consequent development of silicosis are well-known health problems in countries with mining and other dust producing industries. Apart from its direct fibrotic effect on lung tissue, chronic and immunomodulatory character of silica causes susceptibility to tuberculosis (TB) leading to a significantly higher TB incidence in silica-exposed populations. The presence of silica particles in the lung and silicosis may facilitate initiation of tuberculous infection and progression to active TB, and exacerbate the course and outcome of TB, including prognosis and survival. However, the exact mechanisms of the involvement of silica in the pathological processes during mycobacterial infection are not yet fully understood. In this review, we focus on the host's immunological response to both silica and Mycobacterium tuberculosis, on agents of innate and adaptive immunity, and particularly on silica-induced immunological modifications in co-exposure that influence disease pathogenesis. We review what is known about the impact of silica and Mycobacterium tuberculosis or their co-exposure on the host's immune system, especially an impact that goes beyond an exclusive focus on macrophages as the first line of the defense. In both silicosis and TB, acquired immunity plays a major role in the restriction and/or elimination of pathogenic agents. Further research is needed to determine the effects of silica in adaptive immunity and in the pathogenesis of TB

Characterising the potential health risks associated with coal dust

Coal dust is inextricably linked to the development of dust diseases. To date, the role of mineral matter in coal has been investigated for its links to pulmonary damage; however, no consensus has been reached on which characteristics are relevant to pulmonary toxicity. This study hypothesises that the toxic potential of inhalable coal dust can be attributed to reactive mineralogy and the specific surface area for interaction between the particles and primary phagocytes such as macrophages. To test this hypothesis, the study developed an advanced understanding of the relationship between the physicochemical and mineralogical characteristics of coal particles and pulmonary toxicity. Three objectives were constructed to achieve this aim. Objective 1 developed a detailed particle characterisation dataset on coal particle samples utilising both routine (X-ray diffraction and X-ray fluorescence) and advanced methods of coal analysis (automated scanning electron microscopy systems). Objective 2 elucidated multivariant relationships between the particle characteristics and the immunological responses from exposed macrophage cells in vitro using advanced statistical methods. Lastly, objective 3 developed a protocol to empirically characterise the relative risk of coal dust-related damage on a cellular level. In developing a detailed characterisation dataset on the coal samples, both routine and automated analysis tools were used to define general, chemical, mineralogical, and mineral specific characteristics. An auto-SEM-EDS-XRD (Automated scanning electron microscope coupled with Energy Dispersive X-ray Spectroscopy and analyses generated by X-ray Diffraction) protocol was developed to obtain a broad spectrum of particle data by mineralogically mapping each particle. This protocol involved the rigorous analysis of uncertainty in the data using comparative datasets generated from XRD and XRF (X-ray Fluorescence) analyses. In summary, the study demonstrated that the combined use of both routine and advanced particle analysis tools allowed for the classification of chemical and mineralogical distributions as well as a discrimination between general and mineral specific particle characteristics. Generally, these results suggested that features relating to general particle characteristics (size, shape, roughness, and surface area) are more strongly a function of mechanical breakage and deformation than compositional variation. To assess the multivariant relationships between the numerous characteristics defined and response measures of cellular toxicity, a PLSR (partial least squares regression) was applied in a novel approach to attempt a single model comparison of such relationships. This model was chosen for its ability to relate response and explanatory variables based on a new set of variables which have undergone dimensionality reduction whilst maximising the covariance. The results from the relationship analysis showed that physical characteristics (particle shape in particular) displayed a greater influence on cytotoxicity and lipid peroxidation over mineral and chemical-based characteristics. Relating this observation to previous research it was suggested that the influence of shape and roughness on phagocytosis may have strong implications for magnitude of direct and indirect cellular harm and the predominance of either intracellular or extracellular damage. The results also showed that, apart from the influence of particle shape, radical-induced stress and cytotoxicity displayed a strong dependency on (1) the chemical and mineralogical reactivity Ca hosted in gypsum, (2) the release/inhibition of Fe from pyrite and Fe-sulfates, and (3) the surface activity of quartz based on its crystallite size. However, the relationships defined in the context of cytotoxicity displayed a more nuanced dependency with the silicate mineral content and their associated properties compared to lipid peroxidation. From this it was suggested that non-radical related pathways to cytotoxicity could also occur from coal dust exposure. Ultimately, the study demonstrates the first analysis which assesses relative impact and magnitude of multiple particle characteristics on cytotoxicity and cellular stress. Finally, to provide a more easily interpretable format for the analysis of the PLSR relationships, a protocol was developed to screen variables based on: (1) their level of importance to the defined relationship and (2) the rank of importance for each influential variable represented on a unified scale. Elements which explained the variability within the sample characteristics and the responses were clustered using the k-means algorithm to determine classes of samples which display similar characteristics or levels of toxicity. The comparison of the classes grouping samples with similar properties versus samples groups with similar toxicity levels showed that even though samples may share similar properties, their reported level of toxicity may differ. This confirms the observations from previous studies which have shown that the relative toxicity of coal dust cannot be explained on the basis of isolated properties. Rather the set of ‘influential variables' showed that a combination of general, chemical, mineralogical and mineral specific data are needed to determine the differences between levels of toxicity. Ultimately, the application of this protocol on 17 different dust-sized coal samples demonstrated the key differences between samples and their influence on levels of cytotoxicity and lipid peroxidation, which until this study have not been demonstrated by a single regression. As an outcome of such results, this study provides a robust analysis strategy for elucidating particle cell relations which can further advance the understanding of coal dust induced disease pathology. Additionally, the protocol has demonstrated the usefulness of disseminating the complex data structures to more easily interpretable data formats such that a generalisable analysis of risk factors related to coal dust-based cellular damage can be utilised by stakeholders in data-based decision making. Ultimately, the results of this study propose that the toxic potential of coal dust is primarily a function of the reactive mineralogical and chemical components within the particles, however, the magnitude of this intrinsic reactivity is subject to the mitigative factors which can either neutralise of supress the anticipated reactivity

Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation

Acknowledgements We thank Lizette Fick for her contribution to histopathology. We thank Faried Abbass for technical support. We thank the support staff of the Division of Immunology and the Research Animal Facility at the University of Cape Town for their contribution to animal care and technical support. The study was supported by the University of Cape Town, National Research Foundation (South Africa), South African Medical Research Council (SAMRC) National Health Laboratory Service (South Africa), The European Union (contract number: 028190), FP6 NEST project N°028190 “TB REACT”. Research carried out within the scope of the Franco/South African Laboratory “TB Immunity” (Associated International Laboratory ‘AIL’).Peer reviewedPublisher PD

Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88

Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88–/– macrophages and DCs are defective in TNF, IL-12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88–/– mice with MTB is lethal within 4 weeks with 2 log10 higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-γ production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guérin conferred a substantial protection in MyD88–/– mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88–/– mice to control MTB infection

The C-Type Lectin Receptor CLECSF8/CLEC4D Is a Key Component of Anti-Mycobacterial Immunity

Open Access funded by Wellcome Trust: Under a Creative Commons license Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgments We would like to thank S. Hardison, P. Redelinghuys, J. Taylor, C. Wallace, A. Richmond, S. Hadebe, A. Plato, F. Abbass, L. Fick, N. Allie, R. Wilkinson, K. Wilkinson, S. Cooper, D. Lang, and V. Kumar for reagents and assistance, and the animal facility staff for the care of our animals. This work was supported by the MRC (UK) and Wellcome Trust (G.D.B.); MRC (South Africa) and Sydney Brenner Fellowship (M.J.M.); Vici (M.G.N.), Vidi (R.v.C.), and Veni grants (T.S.P.) from the Netherlands Organization for Scientific Research; the Royal Netherlands Academy of Arts and Sciences (T.H.M.O.); EC FP7 projects (NEWTBVAC, ADITEC; T.H.M.O.); Carnegie Corporation and CIDRI (J.C.H.); and the University of Aberdeen (B.K.).Peer reviewedPublisher PD

Prominent role for T cell-derived Tumour Necrosis Factor for sustained control of Mycobacterium tuberculosis infection

Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF-producing CD4+ and CD8+ T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection