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

Larissa D Cunha1, Juliana M Ribeiro1, Talita D Fernandes1

  • 1Department of Cell Biology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Ribeirão Preto, Sao Paulo 14049-900, Brazil.

Nature Communications
|December 22, 2015
PubMed

Insights

Coxiella burnetii inhibits host caspase-1 activation. A novel C. burnetii effector protein, IcaA, interferes with caspase-11-induced inflammasome activation, aiding bacterial replication.

Area of Science:

  • Microbiology
  • Immunology
  • Cell Biology

Background:

  • Coxiella burnetii is an intracellular bacterium that manipulates host cell responses for replication.
  • Caspase-1 and inflammasome activation are critical host defense mechanisms against bacterial pathogens.

Purpose of the Study:

  • To investigate the mechanism by which Coxiella burnetii inhibits host caspase-1 activation.
  • To identify novel C. burnetii factors involved in suppressing inflammasome responses.

Main Methods:

  • Co-infection experiments with C. burnetii and other bacterial species (E. coli, L. pneumophila) in primary mouse macrophages.
  • Genetic screening using L. pneumophila flagellin mutants to identify C. burnetii genes.
  • Analysis of caspase-11 and NLRP3 inflammasome activation.
  • Construction and characterization of icaA deletion mutants of C. burnetii.

Main Results:

  • C. burnetii inhibits caspase-1 activation in macrophages.
  • C. burnetii infection suppresses caspase-11-mediated non-canonical NLRP3 inflammasome activation induced by secondary infections.
  • A novel C. burnetii gene, IcaA, was identified as crucial for inhibiting caspase activation.
  • Expression of IcaA in L. pneumophila inhibited caspase-11 activation.
  • icaA mutants of C. burnetii were attenuated in their ability to suppress inflammasome activation.

Conclusions:

  • IcaA is a novel C. burnetii effector protein secreted via the Dot/Icm type IV secretion system.
  • IcaA interferes with caspase-11-induced, non-canonical inflammasome activation.
  • Inhibition of inflammasome activation by IcaA likely contributes to C. burnetii replication within macrophages.

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