Abstract
Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf -/- ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
Highlights
The intestinal mucosa is a key site limiting microbial access to the body [1, 2]
Earlier work in a mouse model had shown that the gut epithelium expresses a sensor, called NAIP/NLRC4/caspase-1 inflammasome that can detect the pathogen and mount a defense by 12-18h p.i
We found that the caspase-1 inflammasome triggers the production of IL-18, a pro-inflammatory cytokine that appears essential for the PLOS Pathogens | DOI:10.1371/journal.ppat
Summary
The intestinal mucosa is a key site limiting microbial access to the body [1, 2]. some enteropathogenic bacteria, including Salmonella enterica subspecies 1 serovar Typhimurium (S.Tm), have the capacity to overcome the mucosal defenses and utilize the gut as a port of entry. Its chemo-sensors, termed danger recognition receptors, are detecting conserved microbial products (including key virulence factors) and tissue damage inflicted by the infection, boost antimicrobial defense and recruit phagocytic cell populations to eliminate the pathogen and cellular debris [3,4,5] It appears that some "successful" pathogens have evolved mechanisms to evade these innate responses [6, 7]. S.Tm can downregulate expression of flagella and the SPI-1 type III secretion system at systemic sites and may thereby evade (at least partially) the detection by danger recognition receptors, e.g. the NAIP/NLRC4 inflammasome [8,9,10] Such "stealthy" behavior is not an option at sites where the respective virulence factors (or other recognized components) are needed by the pathogen for performing an important step of the infection cycle. It had remained unclear whether and how this is coordinated with other defenses at this critical site
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