Pretreatment of Mice with Streptomycin Provides a<i>Salmonella enterica</i>Serovar Typhimurium Colitis Model That Allows Analysis of Both Pathogen and Host

TLDR

Salmonella enterica serovar Typhimurium causes human enterocolitis, but in mice it fails to provoke intestinal inflammation and instead leads to a systemic typhoid‑like infection, limiting mechanistic studies due to the lack of a suitable murine model. We present streptomycin‑pretreated mice as a model that induces Typhimurium colitis. Using lymphotoxin β‑receptor knockout mice lacking lymph nodes, we show that Peyer's patches and mesenteric lymph nodes are not required for initiating murine Typhimurium colitis. The resulting colitis mirrors human disease with epithelial ulceration, edema, ICAM‑1 induction, and PMN infiltration, depends on the SPI1 type III secretion system, and enables simultaneous use of pathogen and host mutants to dissect enteric salmonellosis mechanisms.

Abstract

ABSTRACT Salmonella enterica subspecies 1 serovar Typhimurium is a principal cause of human enterocolitis. For unknown reasons, in mice serovar Typhimurium does not provoke intestinal inflammation but rather targets the gut-associated lymphatic tissues and causes a systemic typhoid-like infection. The lack of a suitable murine model has limited the analysis of the pathogenetic mechanisms of intestinal salmonellosis. We describe here how streptomycin-pretreated mice provide a mouse model for serovar Typhimurium colitis. Serovar Typhimurium colitis in streptomycin-pretreated mice resembles many aspects of the human infection, including epithelial ulceration, edema, induction of intercellular adhesion molecule 1, and massive infiltration of PMN/CD18 + cells. This pathology is strongly dependent on protein translocation via the serovar Typhimurium SPI1 type III secretion system. Using a lymphotoxin β-receptor knockout mouse strain that lacks all lymph nodes and organized gut-associated lymphatic tissues, we demonstrate that Peyer's patches and mesenteric lymph nodes are dispensable for the initiation of murine serovar Typhimurium colitis. Our results demonstrate that streptomycin-pretreated mice offer a unique infection model that allows for the first time to use mutants of both the pathogen and the host to study the molecular mechanisms of enteric salmonellosis.