Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 41, Pages E8711-E8720Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1707792114
Keywords
M. tuberculosis; autophagy; LC3-associated phagocytosis; NADPH oxidase; LytR-CpsA-Psr
Categories
Funding
- Potts Memorial Foundation
- Stony Wold-Herbert Fund
- NIH/NIAID [AI119670, AI107774, AI064282, AI130454, U19AI109725]
- NYU SOM Nand WUSM
- NIH [1S10OD010582]
- National Cancer Institute [P30 CA91842]
- Institute of Clinical and Translational Sciences/Clinical and Translational Science from the National Center for Research Resources [UL1TR000448]
- NIH
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Mycobacterium tuberculosis' success as a pathogen comes from its ability to evade degradation by macrophages. Normally macrophages clear microorganisms that activate pathogen-recognition receptors (PRRs) through a lysosomal-trafficking pathway called LC3-associated phagocytosis (LAP). Although M. tuberculosis activates numerous PRRs, for reasons that are poorly understood LAP does not substantially contribute to M. tuberculosis control. LAP depends upon reactive oxygen species (ROS) generated by NADPH oxidase, but M. tuberculosis fails to generate a robust oxidative response. Here, we show that CpsA, a LytR-CpsA-Psr (LCP) domain-containing protein, is required for M. tuberculosis to evade killing by NADPH oxidase and LAP. Unlike phagosomes containing wild-type bacilli, phagosomes containing the Delta cpsA mutant recruited NADPH oxidase, produced ROS, associated with LC3, and matured into antibacterial lysosomes. Moreover, CpsA was sufficient to impair NADPH oxidase recruitment to fungal particles that are normally cleared by LAP. Intracellular survival of the Delta cpsA mutant was largely restored in macrophages missing LAP components (Nox2, Rubicon, Beclin, Atg5, Atg7, or Atg16L1) but not in macrophages defective in a related, canonical autophagy pathway (Atg14, Ulk1, or cGAS). The Delta cpsA mutant was highly impaired in vivo, and its growth was partially restored in mice deficient in NADPH oxidase, Atg5, or Atg7, demonstrating that CpsA makes a significant contribution to the resistance of M. tuberculosis to NADPH oxidase and LC3 trafficking in vivo. Overall, our findings reveal an essential role of CpsA in innate immune evasion and suggest that LCP proteins have functions beyond their previously known role in cell-wall metabolism.
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