Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA

Significance Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis, grows in macrophages, cells that normally kill bacteria. Recent work has defined a macrophage pathway called “LC3-associated phagocytosis” (LAP) that can eliminate other microbes. LAP is characterized by the recruitment of NADPH oxidase to phagosomes, followed by phagosomal association with LC3 and delivery of the bacteria to a degradative lysosome. Here, we show that LAP does not effectively clear Mtb. The ability of Mtb to inhibit LAP and therefore cause disease depends upon CpsA, a member of the LytR-CpsA-Psr (LCP) protein family, which has previously been implicated in cell-wall metabolism. We demonstrate that Mtb CpsA plays an unexpected role in antagonizing host innate immunity by inhibiting NADPH oxidase and LAP.