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

Stefan Köster, Sandeep Upadhyay, Pallavi Chandra, Kadamba Papavinasasundaram, Guozhe Yang, Amir Hassan, Steven J. Grigsby, Ekansh Mittal, Heidi S. Park, Victoria Jones, Fong Fu Hsu, Mary Jackson, Christopher M. Sassetti, Jennifer A. Philips

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

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 ΔcpsA 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 ΔcpsA 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 ΔcpsA 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.

Original languageEnglish
Pages (from-to)E8711-E8720
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number41
DOIs
StatePublished - Oct 10 2017

Keywords

  • Autophagy
  • LC3-associated phagocytosis
  • LytR-CpsA-Psr
  • M. tuberculosis
  • NADPH oxidase

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