Abstract
The Nlrc4 inflammasome is triggered in response to contamination of the host cell cytoplasm with bacterial flagellin, which induces pyroptosis, a form of cell death that accounts for restriction of bacterial infections. Although induction of pyroptosis has been extensively investigated in response to Salmonella typhimurium and Legionella pneumophila, little is known regarding the role of the inflammasome for restriction of non-pneumophila Legionella species. Here, we used five species of the Legionella genus to investigate the importance of the inflammasome for restriction of bacterial infection in vivo. By infecting mice deficient for inflammasome components, we demonstrated that caspase-1 and Nlrc4, but not Asc, contribute to restriction of pulmonary infection with L. micdadei, L. bozemanii, L. gratiana, and L. rubrilucens. L. longbeachae, a non-flagellated bacterium that fails to trigger pyroptosis, was not restricted by the inflammasome and induced death in the infected mice. In contrast to L. longbeachae, flagellin mutants of L. pneumophila did not induce mice death; therefore, besides bypassing the Nlrc4 inflammasome, L. longbeachae may employ additional virulence strategies to replicate in mammalian hosts. Collectively, our data indicate that the Nlrc4 inflammasome plays an important role in host protection against opportunistic pathogenic bacteria that express flagellin.
Highlights
Innate immune cells employ germ line encoded pattern recognition receptors (PRRs) that are important for recognition of pathogenassociated molecular patterns (PAMPs), conserved structures present in microbes and pathogens (Janeway and Medzhitov, 2002)
Caspase-1 contributes for restriction of pulmonary infection with Legionella spp. that trigger pyroptosis We have previously demonstrated that to L. pneumophila, other Legionella species such as L. micdadei, L. bozemanii, L. gratiana, and L. rubrilucens express flagellin and trigger pyroptosis in macrophages (Silveira and Zamboni, 2010)
Nlrc4, but not Asc, contributes for growth restriction of Legionella spp. that trigger pyroptosis To investigate which inflammasome was responsible for caspase-1 -dependent restriction of infection with L. micdadei, L. bozemanii, L. gratiana, and L. rubrilucens, we infected mice deficient for Nlrc4 or Asc and measured the CFU in the lungs 48 h after infection
Summary
Innate immune cells employ germ line encoded pattern recognition receptors (PRRs) that are important for recognition of pathogenassociated molecular patterns (PAMPs), conserved structures present in microbes and pathogens (Janeway and Medzhitov, 2002). Studied PRRs are the Toll-like receptors (TLRs), Rig-like receptors (RLRs), and Nod-like receptors (NLRs); this trinity of PRR plays an important role in recognition of bacterial, viruses, fungi, and parasitic infections (Kawai and Akira, 2009; Schroder and Tschopp, 2010). Nod and Nod signaling requires the protein kinase Rip, leading to expression of inflammatory genes, such as those of cytokines and chemokines (Franchi et al, 2008). Other members of the NLR family do not play an evident role in regulation of gene expression. Instead, they participate in the activation of the pro-caspase-1, which will lead to the formation of a multimeric complex called inflammasome (Schroder and Tschopp, 2010).
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