Role for Neutrophils in Host Immune Responses and Genetic Factors That Modulate Resistance to Salmonella enterica Serovar Typhimurium in the Inbred Mouse Strain SPRET/Ei

Abstract

ABSTRACT Infection with Salmonella enterica serovar Typhimurium is a complex disease in which the host-bacterium interactions are strongly influenced by genetic factors of the host. We demonstrate that SPRET/Ei, an inbred mouse strain derived from Mus spretus , is resistant to S. Typhimurium infections. The kinetics of bacterial proliferation, as well as histological examinations of tissue sections, suggest that SPRET/Ei mice can control bacterial multiplication and spreading despite significant attenuation of the cytokine response. The resistance of SPRET/Ei mice to S. Typhimurium infection is associated with increased leukocyte counts in the circulation and enhanced neutrophil influx into the peritoneum during the course of infection. A critical role of neutrophils was confirmed by neutrophil depletion: neutropenic SPRET/Ei mice were sensitive to infection with S. Typhimurium and showed much higher bacterial loads. To identify genes that modulate the natural resistance of SPRET/Ei mice to S. Typhimurium infection, we performed a genome-wide study using an interspecific backcross between C3H/HeN and SPRET/Ei mice. The results of this analysis demonstrate that at least two loci, located on chromosomes 6 and 11, affect survival following lethal infection with S. Typhimurium. These two loci contain several interesting candidate genes which may have important implications for the search for genetic factors controlling Salmonella infections in humans and for our understanding of complex host-pathogen interactions in general.