Neutrophilic inflammation promotes bacterial growth during Tuberculosis

Abstract

Abstract Nitric oxide is generally assumed to protect from tuberculosis by inhibiting the growth of Mycobacterium tuberculosis (Mtb), thereby preventing tissue damage. In contrast, we report that nitric oxide protects the host by repressing a neutrophil recruitment cascade that requires IL-1, CXCR2 and 12-lipoxygenase (12-LOX)-derived eicosanoids. Inhibition of the neutrophil recruitment alone enables the susceptible NOS2 KO mice to control Mtb growth, suggesting that neutrophilic inflammation, not an intrinsic anti-bacterial defect, drives susceptibility. By using a library of bacterial transposon mutants as reporters of host derived stress conditions, we show that granulocytic inflammation generates a nutrient-replete growth-permissive environment for Mtb which obviates the need for essential virulence factors, including the siderophore, mycobactin, and the virulence-related lipid, phthiocerol dimycocerosate, that are otherwise indispensable for establishing infection. A similar inflammatory pathway promotes TB in humans, as human genetic polymorphism that increases 12-LOX expression is associated with TB risk. The concentration of 12-LOX products correlates with neutrophil numbers and bacterial burden in the bronchoalveolar lavage of patients with pulmonary tuberculosis. We propose that Mtb exploits the inflammatory response to preferentially replicate at sites of tissue damage that promote contagion.