Abstract
Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm att, sseD) causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRβ−/−δ−/−, JH −/−, IgA−/−, pIgR−/−). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using ‘L-mice’ which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm att from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most “classical” immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission.
Highlights
Bacterial diarrhea is a global cause of morbidity and mortality
Sm-treated mice recover from S. tmatt induced gut inflammation and display extensive differences in the kinetics of fecal pathogen clearance In sm-treated mice, infection with an attenuated S. typhimurium strain (S. typhimurium SL1344 sseD; termed S. tmatt; Table S1) is known to recapitulate key aspects of the early stages of human non-typhoidal Salmonella (NTS) diarrhea, i.e. gut inflammation 8h after orogastric exposure with infection confined to the gastrointestinal tract [22]
Symptoms of the acute gut inflammation usually decline by 5–7 days after infection [23]. If this model may be useful to dissect the role of pathogen-specific secretory IgA (sIgA) and the intestinal microbiota in pathogen clearance at the final stage of a primary infection we analyzed the outcome of long-term S. tmatt infections [6,24]
Summary
Bacterial diarrhea is a global cause of morbidity and mortality. In most cases, the acute disease symptoms cease after a few days and the pathogen is eliminated from the gut. The mechanisms eliminating enteropathogenic bacteria from the gut lumen are poorly understood. In addition to the host’s immune system, the highly dense and diverse bacterial community in the gut (the microbiota; .500 different species [1,2]) plays a key role by inhibiting pathogen growth in the gut lumen right from the beginning. This phenomenon is referred to as ‘colonization resistance’ and efficiently blocks infections by Clostridium difficile, Salmonella spp. and many other pathogenic bacteria [3]. Colonization resistance might be based on nutrient limitation, release of inhibitory metabolites, production of bactericidal compounds, the competition for binding sites and other, unidentified features of the dense microbial community [4,5]
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