Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses

Abstract

Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus–challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

“…TNFAIP8 expression is induced by TNF, 20 promotes tumor metastasis and is a risk factor for non-Hodgkin's lymphoma in humans and bacterial infection in mice. 21,22 Similarly, TIPE2 regulates both carcinogenesis and inflammation, and its germline deletion leads to leukocytosis and systemic inflammatory disorders in aged, 129-strain mice. 18,23 Moreover, TIPE1 has been reported to regulate cell death, 24 whereas the oncogenic role of TIPE3 has just been characterized by us.…”

The genetic basis for individual differences in mRNA splicing and APOBEC1 editing activity in murine macrophages

“…The widely used laboratory inbred A/J (AJ) and C57BL/6J (B6) mice display variable susceptibility to a variety of infectious agentssuch as Staphylococcus aureus, T. gondii, and Trypanosoma cruzi (McLeod et al 1989;Parekh et al 1998;Ahn et al 2010;Silva et al 2013)-and inflammatory pathologies such as atherosclerosis, obesity, and type 2 diabetes (Paigen et al 1985;Surwit et al 1988;Surwit et al 1995). These phenotypic differences often replicate in the AXB/BXA RI mice, derived from an initial reciprocal cross of AJ and B6 mice followed by multiple rounds ($20) of inbreeding (Nesbitt and Skamene 1984;Marshall et al 1992).…”

TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection

“…However, the mechanisms whereby microbes promote them are not well understood. TIPE2, or tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TNFAIP8L2), is a member of the TNFAIP8 family, which is preferentially expressed in hematopoietic cells (12)(13)(14)(15)(16)(17)(18). It is significantly down-regulated in patients with infectious or autoimmune disorders (15,19).…”