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

Author(s)

Cunha, Larissa D. ^[1] ; Ribeiro, Juliana M. ^[1] ; Fernandes, Talita D. ^[1] ; Massis, Liliana M. ^[1] ; Khoo, Chen Ai ^[2] ; Moffatt, Jennifer H. ^[2] ; Newton, Hayley J. ^[2] ; Roy, Craig R. ^[3] ; Zamboni, Dario S. ^[1]

Affiliation

^[1] Univ Sao Paulo FMRP USP, Med Sch Ribeirao Preto, Dept Cell Biol, BR-14049900 Sao Paulo - Brazil

^[2] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic 3000 - Australia

^[3] Yale Univ, Dept Microbial Pathogenesis, Sch Med, New Haven, CT 06536 - USA

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 6, DEC 2015.
• Web of Science Citations: 27

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. (AU)

• FAPESP's process: 14/50268-2 - Deciphering the interactions between Legionella longbeachae and eukaryotic host cells
• Grantee: Dario Simões Zamboni
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/04684-4 - The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion
• Grantee: Dario Simões Zamboni
• Support Opportunities: Research Projects - Thematic Grants