Along with respiratory tract disease per se , viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 post-infection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived, products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza infection can remotely impair the gut’s barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.
Summary Inflammasomes are signaling platforms that are assembled in response to infection or sterile inflammation by cytosolic pattern recognition receptors (PRRs). The consequent inflammasome-triggered Caspase-1 activation is critical for the host defense against pathogens. During infection, NLRP3, a PRR also called Cryopyrin, triggers the assembly of an inflammasome activating Caspase-1 via the recruitment of ASC and Nek7. The NLRP3 inflammasome activation is tightly controlled both transcriptionally and post-translationally. Despite the importance of the NLRP3 inflammasome regulation in autoinflammatory and infectious diseases, little is known about the mechanism controlling the NLRP3 activation and the upstream signaling that regulates the NLRP3 inflammasome assembly. We have previously shown that the RhoGTPases-activating toxin from Escherichia coli , CNF1, activates Caspase-1, but the upstream mechanism is unclear. Here we provide evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activate host RhoGTPases. We demonstrate that this activation relies on monitoring of the toxin’s activity on the RhoGTPase Rac2. We also show that the NLRP3 inflammasome is activated by a signaling cascade involving the P21 activated kinases (Pak) 1/2 and the Pak1-mediated phosphorylation of Threonine 659 of NLRP3, which is necessary for the NLRP3-Nek7 interaction, the inflammasome activation and the IL-1ß cytokine maturation. Furthermore, inhibition of the Pak-NLRP3 axis diminishes the bacterial clearance of CNF1-expressing UTI89 E . coli during bacteremia in mice. Altogether, our results establish Pak1/2 as critical regulators of the NLRP3 inflammasome and reveal the role of the Pak-NLRP3 signaling axis in vivo during bacteremia in mice.
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