Abstract
Inflammasomes can prevent systemic dissemination of enteropathogenic bacteria. As adapted pathogens including Salmonella Typhimurium (S. Tm) have evolved evasion strategies, it has remained unclear when and where inflammasomes restrict their dissemination. Bacterial population dynamics establish that the NAIP/NLRC4 inflammasome specifically restricts S. Tm migration from the gut to draining lymph nodes. This is solely attributable to NAIP/NLRC4 within intestinal epithelial cells (IECs), while S. Tm evades restriction by phagocyte NAIP/NLRC4. NLRP3 and Caspase-11 also fail to restrict S. Tm mucosa traversal, migration to lymph nodes, and systemic pathogen growth. The ability of IECs (not phagocytes) to mount a NAIP/NLRC4 defense in vivo is explained by particularly high NAIP/NLRC4 expression in IECs and the necessity for epithelium-invading S. Tm to express the NAIP1-6 ligands—flagella and type-III-secretion-system-1. Imaging reveals both ligands to be promptly downregulated following IEC-traversal. These results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.
Highlights
Oral bacterial infection causes localized gastrointestinal disease, but pathogen dissemination to systemic sites can lead to life-threatening complications
The size of a pathogen population inside the mesenteric lymph nodes (mLN) is the product of several parameters, i.e., bacterial immigration to this site, replication on the way to and within the organ, emigration to other sites and elimination of the pathogen by the host
In contrast to classical selective plating of infected organs, which merely provides a snapshot of the bacterial population size, infections with mixtures of wild-type isogenic tagged strains (WITS), combined with mathematical modeling can reveal the dynamic parameters and thereby provide essential information on pathogen restrictive mechanisms (Fig S1).[58,59,60,61,62,63]
Summary
Oral bacterial infection causes localized gastrointestinal disease, but pathogen dissemination (from here on termed migration) to systemic sites can lead to life-threatening complications. Multiple host defenses cooperate to limit mucosal infection and pathogen spread.[1] The intestinal mucus lining and antimicrobial peptide secretion restrict mucosal invasion.[2,3,4,5,6,7] Intestinal epithelial cells (IECs) and lamina propria phagocytes mount cell-intrinsic programs and release pro-inflammatory signals to counter pathogens that breach this first barrier.[2,8,9,10,11] Diverse immune cell types patrol systemic organs and prevent excessive pathogen replication.[12,13,14,15] This multilayered host defense is triggered by pattern recognition receptors (PRRs) that detect pathogenassociated molecular patterns (PAMPs), exposed by invading microbes. It is not fully understood which innate defense mechanisms act at which stage of the infection in vivo and what quantitative impact can be assigned to each layer of the defense
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