5 years ago

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

tuberculosis, we studied

tuberculosis, we studied the microbicidal activity of human peripheral blood neutrophils against virulent and attenuated mycobacteria in vitro. Human neutrophils readily phagocytosed serumopsonized M. tuberculosis with high efficiency and became activated. However, despite induction of antibacterial effectors, which otherwise effectively killed avirulent M. smegmatis, virulent M. tuberculosis survived inside neutrophils. We observed that survival of virulent M. tuberculosis was accompanied by necrotic cell death of neutrophils. Cell death entirely depended on production of radical oxygen species (ROS), since CGD neutrophils were protected from necrosis upon M. tuberculosis infection. More importantly, the M. tuberculosis ΔRD1 mutant failed to induce neutrophil necrosis and became susceptible to ROS-mediated killing. Despite activation by mycobacteria, neutrophils fail to kill virulent M. tuberculosis and succumb to necrotic cell death in a strictly ROS and RD1 dependent manner. We conclude that this novel virulence mechanism of M. tuberculosis to escape killing by neutrophils is instrumental in the pathogenesis of tuberculosis. Biography: Bjorn Corleis, PhD joined Dr. Douglas Kwon’s lab at the Ragon Institute of MGH, MIT and Harvard as a Research Fellow in 2012. He currently focuses on immune responses against HIV at gut-associated lymphoid tissue and HIV/TB co-infection in the lung. Dr. Corleis graduated from the London School of Hygiene and Tropical Medicine under the supervision of Prof. Dr. Ulrich Schaible. During his PhD, he focused on human neutrophils in tuberculosis. 3) Nitric oxide controls tuberculosis immunopathology by inhibiting NLRP3 inflammasome-dependent IL-1� processing Bibhuti B. Mishra 1 , Vijay A. K. Rathinam 3 , Gregory W. Martens 2 , Hardy Kornfeld 2 , Katherine A. Fitzgerald 3 1, 4 , and Christopher M. Sassetti 1 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA; 2 Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Massachusetts Medical School, Worcester, MA; 3 Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA; 4 Howard Hughes Medical Institute, Chevy Chase, MD Interleukin-1 (IL-1) is an important mediator of innate immunity, but can also promote inflammatory tissue damage. During persistent infections, such as tuberculosis, the beneficial antimicrobial role of this cytokine must be balanced with the need to prevent neutrophilmediated immunopathology. To differentiate the antimicrobial and pathological roles of this cytokine, we employed a streptomycin-dependent Mycobacterium tuberculosis (Mtb 18b) infection model, where bacterial replication can be controlled by selective administration and subsequent withdrawal of streptomycin. By exogenously controlling the replication of Mtb in vivo, we obviated the requirement for antimicrobial immunity and discovered that IL-1 was responsible for neutrophil influx into the infected lung. In wild type animals, the both IL-1 production and infection-induced immunopathology were suppressed by lymphocyte-derived IFN�. This effect was directly mediated by nitric oxide (NO), which we found to specifically inhibit the assembly of the NLRP3 inflammasome in infected macrophages via thiol nitrosylation. This mechanism also appears to suppress pathology in vivo, as we found that the exacerbated inflammatory response seen in iNOS -/- mice depended on the processing of IL-1 by the inflammasome. These data rationalize the differential importance of the inflammasome for IL-1 production in vivo and in vitro. We propose that the NO produced as a result of adaptive immunity plays an indispensable role in modulating destructive innate inflammatory responses that are elicited by chronic infection. This work was supported by National institute of Health Grant AI-064282 and Howard Hughes Medical Institute. 13

Biography: Bibhuti Mishra, PhD is a Post-doctoral fellow in Christopher Sassetti’s lab at the University of Massachusetts Medical School, Worcester. He received his PhD in Pharmacy with specialization in Molecular Cell Biology from the University of Lisbon, Portugal. Dr Mishra’s research focuses on understanding the immunological mechanisms of tissue damage control during tuberculosis. 14

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