Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome

Abstract

The mammalian innate immune system uses Toll-like receptors (TLRs) and Nod-LRRs (NLRs) to detect microbial components during infection. Often these molecules work in concert; for example, the TLRs can stimulate the production of the proforms of the cytokines IL-1β and IL-18, whereas certain NLRs trigger their subsequent proteolytic processing via caspase 1. Gram-negative bacteria use type III secretion systems (T3SS) to deliver virulence factors to the cytosol of host cells, where they modulate cell physiology to favor the pathogen. We show here that NLRC4/Ipaf detects the basal body rod component of the T3SS apparatus (rod protein) from S. typhimurium (PrgJ), Burkholderia pseudomallei (BsaK), Escherichia coli (EprJ and EscI), Shigella flexneri (MxiI), and Pseudomonas aeruginosa (PscI). These rod proteins share a sequence motif that is essential for detection by NLRC4; a similar motif is found in flagellin that is also detected by NLRC4. S. typhimurium has two T3SS: Salmonella pathogenicity island-1 (SPI1), which encodes the rod protein PrgJ, and SPI2, which encodes the rod protein SsaI. Although PrgJ is detected by NLRC4, SsaI is not, and this evasion is required for virulence in mice. The detection of a conserved component of the T3SS apparatus enables innate immune responses to virulent bacteria through a single pathway, a strategy that is divergent from that used by plants in which multiple NB-LRR proteins are used to detect T3SS effectors or their effects on cells. Furthermore, the specific detection of the virulence machinery permits the discrimination between pathogenic and nonpathogenic bacteria.

Gut–Liver Axis: Role of Inflammasomes

“…[32][33][34] However, the mechanism involving activation of this inflammasome is not yet fully understood. Although other NLR proteins, such as murine 143 NAIP5 and NAIP2 also interact with bacterial flagellin or type III secretion system (T3SS), it is the rod components that cause the assembly and activation of NLRC4 inflammasome.…”

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

“…The necessity of adaptor ASC (apoptosis-associated specklike protein containing a CARD) engagement for diverse effects will be summarized. Some interesting aspects haveadditional PAMPs trigger NLRC4-mediated caspase-1 activation [10], which eventually led to the identification of the components of the type III secretion system (T3SS) as additional activators of NLRC4 [12][13][14][15]. NLRC4 thus mediates cell response to needle and rod proteins, the components of T3SS, and to flagellin.…”

O papel da flagelina e do sistema de secreção de Escherichia coli enteroinvasora na resposta imune inata dos macrófagos

“…A ativação de caspase-1, induzida por Shigella, foi previamente atribuída à IpaB (HILBI et al, 1998 CASE et al, 2009;MIAO et al, 2010a;MIAO et al, 2010b;ZHAO et al, 2011). Figura 6.…”

“…Um estudo recente demonstrou que as proteínas do aparato do sistema de secreção do tipo III (proteínas Rod), de alguns patógenos, incluindo Salmonella, Pseudomonas e Shigella, são capazes de induzir a ativação de caspase-1 via inflamassoma IPAF (MIAO et al, 2010b). Esses dados podem justificar a deficiência na ativação de caspase-1 da EIEC incapaz de montar o sistema de secreção (Figura 17 e 19), sugerindo que a proteína do aparato do sistema de secreção de EIEC seja um possível agonista do receptor IPAF envolvido na ativação da caspase-1.…”

“…Esses estudos indicam que IPAF é o receptor-chave envolvido no processo de morte celular de macrófagos por Salmonella, dependente de caspase-1. Estudo recente, in vivo, mostrou que a morte rápida dos macrófagos por piroptose (dependente de caspase-1) é crucial para controlar a infecção por Salmonella, uma vez que essas bactérias, escapando dos macrófagos são fagocitadas e mortas pelos neutrófilos (resposta Th17) (MIAO et al, 2010b).…”