Identification of new loci involved in the host susceptibility to Salmonella Typhimurium in collaborative cross mice

Jing Zhang,Richard Mott,Jean-Jacques Panthier,Danielle Malo,Jean Jaubert,Xavier Montagutelli

doi:10.1186/s12864-018-4667-0

Abstract

BackgroundSalmonella is a Gram-negative bacterium causing a wide range of clinical syndromes ranging from typhoid fever to diarrheic disease. Non-typhoidal Salmonella (NTS) serovars infect humans and animals, causing important health burden in the world. Susceptibility to salmonellosis varies between individuals under the control of host genes, as demonstrated by the identification of over 20 genetic loci in various mouse crosses. We have investigated the host response to S. Typhimurium infection in 35 Collaborative Cross (CC) strains, a genetic population which involves wild-derived strains that had not been previously assessed.ResultsOne hundred and forty-eight mice from 35 CC strains were challenged intravenously with 1000 colony-forming units (CFUs) of S. Typhimurium. Bacterial load was measured in spleen and liver at day 4 post-infection. CC strains differed significantly (P < 0.0001) in spleen and liver bacterial loads, while sex and age had no effect. Two significant quantitative trait loci (QTLs) on chromosomes 8 and 10 and one suggestive QTL on chromosome 1 were found for spleen bacterial load, while two suggestive QTLs on chromosomes 6 and 17 were found for liver bacterial load. These QTLs are caused by distinct allelic patterns, principally involving alleles originating from the wild-derived founders. Using sequence variations between the eight CC founder strains combined with database mining for expression in target organs and known immune phenotypes, we were able to refine the QTLs intervals and establish a list of the most promising candidate genes. Furthermore, we identified one strain, CC042/GeniUnc (CC042), as highly susceptible to S. Typhimurium infection.ConclusionsBy exploring a broader genetic variation, the Collaborative Cross population has revealed novel loci of resistance to Salmonella Typhimurium. It also led to the identification of CC042 as an extremely susceptible strain.

Highlights

Salmonella is a Gram-negative bacterium causing a wide range of clinical syndromes ranging from typhoid fever to diarrheic disease
Significant advances in understanding the host response to Salmonella infection have been made over the years with the identification of genes such as Slc11a11 (Nramp1), Tlr4 and Btk, first in the mouse model [12,13,14,15] and later in other animal species [16, 17]
We identified CC042/GeniUnc (CC042) as an unusually susceptible Collaborative Cross (CC) strain that may have further use as a model for studying Salmonella Typhimurium infection

Summary

Introduction

Salmonella is a Gram-negative bacterium causing a wide range of clinical syndromes ranging from typhoid fever to diarrheic disease. Salmonella is a Gram-negative bacterium responsible for typhoid fever and diarrheic disease It is one of the leading causes of food-borne infections and remains a major threat for human population [1,2,3]. Non-typhoidal Salmonella (NTS) serovars, especially Salmonella enterica serovar Typhimurium, infect both humans and animals, cause a significant disease burden with an estimated 93.8. Significant advances in understanding the host response to Salmonella infection have been made over the years with the identification of genes such as Slc11a11 (Nramp1), Tlr and Btk, first in the mouse model [12,13,14,15] and later in other animal species [16, 17]. BTK tyrosine-protein kinase plays a critical role in the regulation of B cell receptor signaling [5, 18]

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