Abstract
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.
Highlights
Salmonella enterica, an intracellular Gram-negative bacterium, is the causative agent for a wide spectrum of clinical diseases with manifestations ranging from asymptomatic carriers, self-limiting gastroenteritis to fatal systemic infection [1, 2]
We have previously studied the phenotypic impact of these two sub-loci [16], and in order to further characterize the genetic networks that are affected by the MOLF/Ei allele at the Ity3 locus, we have used a microarray expression approach
These two sub-congenic strains were selected because they carry either the MOLF/Ei alleles at Ity3.1 (Ity3.RecG) or at Ity3.2 sub-locus (Ity3.RecN ), which result in an intermediate survival phenotype after infection with Salmonella typhimurium [16]
Summary
Salmonella enterica, an intracellular Gram-negative bacterium, is the causative agent for a wide spectrum of clinical diseases with manifestations ranging from asymptomatic carriers, self-limiting gastroenteritis to fatal systemic infection [1, 2]. Salmonella is a natural pathogen of mice and infection with Salmonella typhimurium results in a typhoid-like systemic disease. This murine experimental model has been used to identify several genes and pathways involved in disease pathogenesis [5,6,7,8,9]. As there is limited genetic variation within the classical inbred strains, the use of wild-derived strains of mice, such as MOLF/Ei contributes added genetic diversity and has allowed for the identification of novel genes that play an important role in innate immunity [10,11,12,13]. The wild-derived mouse strain, MOLF/Ei is susceptible to infection despite carrying functional copies of genes known to be important in Salmonella infection, such as Slc11a1 and Tlr (toll-like receptor 4) [6, 10]
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