TY - JOUR T1 - The Phagocyte Oxidase Controls Tolerance to <em>Mycobacterium tuberculosis</em> infection JF - bioRxiv DO - 10.1101/232777 SP - 232777 AU - Andrew J Olive AU - Clare M Smith AU - Michael C Kiritsy AU - Christopher M Sassetti Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/12/21/232777.abstract N2 - Protection from infectious disease relies on two distinct mechanisms. “Antimicrobial resistance” directly inhibits pathogen growth, whereas “infection tolerance” controls tissue damage. A single immune-mediator can differentially contribute to these mechanisms in distinct contexts, confounding our understanding of protection to different pathogens. For example, the NADPH-dependent phagocyte oxidase complex (Phox) produces anti-microbial superoxides and protects from tuberculosis in humans. However, Phox-deficient mice do not display the expected defect in resistance to M. tuberculosis leaving the role of this complex unclear. We re-examined the mechanisms by which Phox contributes to protection from TB and found that mice lacking the Cybb subunit of Phox suffered from a specific defect in tolerance, which was due to unregulated Caspase1 activation, IL-1β production, and neutrophil influx into the lung. These studies demonstrate that Phox-derived superoxide protect against TB by promoting tolerance to persistent infection, and highlight a central role for Caspase1 in regulating TB disease progression. ER -