Crif1 Is Associated With Susceptibility to Staphylococcus aureus Infection Through Regulating Host Cell Apoptosis
Year: 2015
Type: article
Abstract: Background. We previously showed that chromosome 8 of A/J mice was responsible for susceptibility to S. aureus infection (Ahn PLOS Pathogens, 2010). However, the specific genes responsible for this susceptibility are unknown. Methods. Chromosome substitution strain (CSS8, chr. 8 from A/J but otherwise C57BL/6J) and N2 backcross mice (F1 [C8A] × C57BL/6J) were applied. Quantitative trait loci (QTL) analysis of S. aureus-infected N2 backcross mice was used to identify gene regions on Chr. 8 associated with susceptibility. Genes in the significant QTL region were evaluated using whole-genome expression data from 1) S. aureus-infected mice and 2) humans with S. aureus bloodstream infection (BSI). Genes identified by all 3 strategies were further analyzed for their apoptotic function with siRNA knockdown. Results. One QTL region on chr. 8 containing 161 genes was significantly associated with susceptibility to S. aureus infection (83180780-88103009). Of these 161 genes, 7 were differentially expressed between: a) S. aureus-infected A/J (susceptible) and C57BL/6J (resistant) mice; and b) patients with S. aureus BSI (n = 32) and healthy subjects (n = 44) (Asf1b, Crif1, Dnaja2, Farsa, Inpp4b, Prdx2, and Tnpo2). Flow cytometry analysis found increased late apoptosis in bone marrow derived macrophages (BMDMs) from A/J, CSS8 versus C57BL/6J at both naive (25.8% and 18.7% versus 12.6%; P < .05) and S. aureus-infected status (23.2% and 16.7% versus 10.2%; P < .05). Down-regulation of Crif1 by siRNA in BMDMs increased apoptosis (38.3%) compared with scramble siRNA (17.3%) at the naive status (P <.05). Stimulation by S. aureus induced even higher apoptosis, with 40.6% for Crif1 siRNA and 32.3% for scramble siRNA (P < .05). Finally, real-time PCR confirmed that Crif1 was down-regulated in A/J mice before and after S. aureus infection. Conclusion. These findings suggest that Crif1 contributes to susceptibility to S. aureus infection in mice by affecting host cell apoptosis and indicate its involvement in human response to S. aureus infection. Disclosures. C. W. Woods, Becton Dickinson: Grant Investigator and Scientific Advisor, Consulting fee and Research support. Becton Dickinson: Grant Investigator and Scientific Advisor, Consulting fee and Research support. bioMerieux: Investigator and Scientific Advisor, Consulting fee, Research grant and Speaker honorarium. Nanosphere: Scientific Advisor, Consulting fee. bioMerieux: Investigator and Scientific Advisor, Consulting fee, Research grant and Speaker honorarium. Cempra: Investigator, Research support. Nanosphere: Scientific Advisor, Consulting fee. Cubist: Investigator, Research support. Bill and Melinda Gates Foundation: Grant Investigator, Research grant. Cempra: Investigator, Research support. DARPA: Grant Investigator, Research grant. Cubist: Investigator, Research support. Defense Threat Reduction Agency: Research Contractor, Research support. Bill and Melinda Gates Foundation: Grant Investigator, Research grant. National Institute of Allergy and Infectious Diseases (NIAID): Research Contractor, Research support. DARPA: Grant Investigator, Research grant. Defense Threat Reduction Agency: Research Contractor, Research support. NIAID: Research Contractor, Research support
Source: Open Forum Infectious Diseases
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,053
OpenAlex ID: W2292824083