Why macrophages cannot LAP up TB

ABSTRACTM. tuberculosis causes an enormous worldwide burden of disease. Its success depends upon subverting the antimicrobial capacity of macrophages. We have known for decades that M. tuberculosis impairs phagosomal trafficking to avoid lysosomal degradation, but the mechanism is unclear. Recent work has described a phagolysosomal pathway called LC3-associated phagocytosis (LAP), in which LC3 associates with microbe-containing phagosomes. Macrophage pathogen recognition receptors (PRRs) initiate LAP, and NADPH oxidase and RUBCN/RUBICON are required for LAP. We discovered that CpsA, an exported M. tuberculosis virulence factor, blocks LAP by interfering with recruitment of CYBB/NOX2 (cytochrome b-245, beta polypeptide) to the mycobacterial phagosome. In macrophages and in mice, M. tuberculosis mutants lacking cpsA are successfully cleared by NADPH oxidase and the ensuing LC3-associated lysosomal trafficking pathway. CpsA belongs to the LytR-CpsA-Psr family, which is found widely in Gram-positive bacilli. ...