Abstract
We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780–88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.
Highlights
An emerging body of evidence supports the concept that human genetic variation can influence host susceptibility to and outcome of infectious diseases
The A/J derived allele on chromosome 8 that is responsible for S. aureus susceptibility is dominant, and F1 mice of CSS8 × C57BL/6J were susceptible to S. aureus [6]
These findings suggest that reduced Crif1 expression in A/J and CSS8 mice may contribute to their susceptibility to S. aureus infection through enhanced cellular apoptosis
Summary
An emerging body of evidence supports the concept that human genetic variation can influence host susceptibility to and outcome of infectious diseases. A/J is highly susceptible to S. aureus infection while C57BL/6J is resistant [9]. These two strains provide a unique platform to investigate the host genetic determinants associated with susceptibility to S. aureus infection. Using these strains, we previously reported that the genetic determinants of susceptibility to S. aureus in A/ J mice localized to chromosomes 8, 11, and 18 [6, 8] and identified candidate susceptibility genes on chromosomes 11 [8] and 18 [6]
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