Abstract
Bacterial pathogens utilize pore-forming toxins or sophisticated secretion systems to establish infection in hosts. Recognition of these toxins or secretion system by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, the multiprotein complexes necessary for caspase-1 activation and the maturation of inflammatory cytokines such as IL-1β or IL-18. Here we demonstrate that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. Furthermore, we identify T3SS1 secreted effector proteins, VopQ and VopS, which induce autophagy and the inactivation of Cdc42, respectively, to prevent mainly NLRC4 inflammasome activation. VopQ and VopS interfere with the assembly of specks in infected macrophages. These data suggest that bacterial effectors interfere with inflammasome activation and contribute to bacterial evasion from the host inflammatory responses.
Highlights
The innate immune responses play important roles in host defense against the infection by microbial pathogens
A number of bacterial factors that play a role in V. parahaemolyticus virulence have been characterized, yet little is known about the host factors contributing to the disease process and susceptibility to these pathogens
In this work we found that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection
Summary
The innate immune responses play important roles in host defense against the infection by microbial pathogens. Several nucleotide-binding, oligomerization domain (NOD) leucine-rich repeat proteins (NLRs) and PYHIN proteins, such as NLRP1, NLRP3, NLRC4, AIM2, and IFI16, form inflammasomes: the multiprotein complexes that induce caspase-1 activation by functioning as sensors of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) [1,2,3]. Caspase-1 activation triggers a rapid proinflammatory cell death known as pyroptosis. The NLRC4 inflammasome is activated in response to bacterial flagellin or rod protein, an essential component of the type III secretion system (T3SS) of Gram-negative bacteria. Flagellin that has been delivered into the cytoplasm of infected cells by the T3SS or type IV secretion system (T4SS) can bind to NAIP5 and facilitate NAIP5-NLRC4 interaction following the triggering of NLRC4 inflammasome assembly. Rod protein such as PrgJ of Salmonella enterica delivered by the T3SS can bind to NAIP2 and promote NAIP2-NLRC4 interaction [4,5].
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