Role for Neutrophils in Host Immune Responses and Genetic Factors That Modulate Resistance toSalmonella entericaSerovar Typhimurium in the Inbred Mouse Strain SPRET/Ei

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 hostpathogen interactions in general.

Schistosoma mansoniexperimental infection inMus spretus(SPRET/EiJ strain) mice

“…In fact, published studies have shown that mast cells and eosinophils are able to produce IL-4 and modulate granuloma formation in S. mansoni infection [7, 10]. It has also been confirmed that SPRET/EiJ mice show a high level of resistance to infection of other pathogens like Salmonella enterica where macrophages and neutrophils also play a critical role [4]. Previous studies showed that SPRET/EiJ strain is also strongly resistant to inflammation induced either by cytokines or by bacterial products [27].…”

LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome

“…Sepsis remains one of the leading causes of death in intensive care units (Vincent et al, 2006) and new therapeutic approaches are urgently needed (Riedemann et al, 2003). We previously showed that SPRET/Ei mice are highly resistant to the lethal effects of LPS (Mahieu et al, 2006), as well as to certain bacterial infections (Dejager et al, 2010a). LPS‐induced lethal inflammation and bacterial infections are often used to study the pathogenesis of sepsis (Dejager et al, 2011).…”

“…The great genetic diversity between Mus spretus and Mus musculus has already been instrumental in the identification of genetic loci that contribute to resistance phenotypes of Mus spretus ‐derived strains (Dejager et al, 2009), such as resistance to infection with Salmonella typimurium (Dejager et al, 2010a) and Yersinia pestis (Blanchet et al, 2011). Here, we identified two QTL determining the resistance of SPRET/Ei mice to LPS, one of which is located on the X chromosome.…”

“…We have been studying the mouse strain SPRET/Ei, derived from Mus spretus , to find new molecular players in LPS‐induced inflammation. Among their many different phenotypes (Dejager et al, 2009), SPRET/Ei (S) mice exhibit a remarkable resistance to LPS (Dejager et al, 2010b; Mahieu et al, 2006) and to Gram‐negative infections (Dejager et al, 2010a) compared to the commonly used laboratory mouse strain, C57BL/6 (B). These phenotypes make this strain useful for identifying new molecular targets for the treatment of sepsis.…”

Nuevas herramientas para el estudio de la esquistosomosis: valoración de nuevos fármacos y estudio de la susceptibilidad a la infección

“…Published studies have shown that mast cells and eosinophils are able to produce IL-4 and modulate granuloma formation (Gessner, et al, 2005. In addition, it has also been demonstrated that SPRET/Ei mice showed a high level of resistance to 6 infection of other pathogens, like Salmonella enterica, where macrophages and neutrophils play a critical role in controlling invading pathogens in the periphery by phagocytosis and the production of antimicrobial proteins (Dejager, et al, 2010). Furthermore, previous studies showed that SPRET/Ei is also strongly resistant to inflammation induced either by cytokines or by bacterial products (Turcotte, et al, 2006).…”