Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA

Nat Commun. 2015 Dec 21:6:10205. doi: 10.1038/ncomms10205.

Abstract

Coxiella burnetii is a highly infectious bacterium that promotes its own replication in macrophages by inhibiting several host cell responses. Here, we show that C. burnetii inhibits caspase-1 activation in primary mouse macrophages. By using co-infection experiments, we determine that the infection of macrophages with C. burnetii inhibits the caspase-11-mediated non-canonical activation of the NLRP3 inflammasome induced by subsequent infection with Escherichia coli or Legionella pneumophila. Genetic screening using flagellin mutants of L. pneumophila as a surrogate host, reveals a novel C. burnetii gene (IcaA) involved in the inhibition of caspase activation. Expression of IcaA in L. pneumophila inhibited the caspase-11 activation in macrophages. Moreover, icaA(-) mutants of C. burnetii failed to suppress the caspase-11-mediated inflammasome activation induced by L. pneumophila. Our data reveal IcaA as a novel C. burnetii effector protein that is secreted by the Dot/Icm type IV secretion system and interferes with the caspase-11-induced, non-canonical activation of the inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • Caspases / genetics
  • Caspases / immunology
  • Caspases, Initiator
  • Coxiella burnetii / genetics
  • Coxiella burnetii / immunology*
  • Female
  • Gene Expression Regulation, Bacterial
  • Humans
  • Inflammasomes / immunology*
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Q Fever / genetics
  • Q Fever / immunology*
  • Q Fever / microbiology
  • Type IV Secretion Systems / genetics
  • Type IV Secretion Systems / immunology*

Substances

  • Bacterial Proteins
  • Inflammasomes
  • Type IV Secretion Systems
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator