691. Crif1 Is Associated with Susceptibility to Staphylococcus aureus Infection through Regulating Host Cell Apoptosis
Session: Oral Abstract Session: Infectious Diseases Pathogenesis and Immunity
Friday, October 9, 2015: 8:30 AM
Room: 5--AB
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. aureusbloodstream 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 vs C57BL/6J at both naïve (25.8% and 18.7% vs. 12.6%; p<0.05) and S. aureus-infected status (23.2% and 16.7% vs 10.2%; p<0.05). Down-regulation of Crif1 by siRNA in BMDMs increased apoptosis (38.3%) as compared with scramble siRNA (17.3%) at the naïve status (p<0.05). Stimulation by S. aureus induced even higher apoptosis, with 40.6% for Crif1 siRNA and 32.3% for scramble siRNA (p<0.05). Finally, real-time PCR confirmed that Crif1 was down-regulated in A/J mice before and post 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.

Qin Yan, PhD1, Sunhee Ahn, PhD2, Batu K Sharma-Kuinkel, PhD1, Ephraim L. Tsalik, MD, PhD1,3,4, Derek D Cyr, PhD3, Christopher W Woods, MD, MPH, FIDSA1,3,5, Joshua T. Thaden, MD, PhD1, Robert Qi, MD1, Michael Hu, BS1, Felicia Ruffin, RN, MSN1, Emily Hecker, RN, MSN6 and Vance G. Fowler Jr., MD1,3,7, (1)Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, NC, (2)Department of Biochemistry School of Dentistry, Chonnam National University, Bukgu, South Korea, (3)Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, (4)Emergency Medicine Service, Durham VA Medical Center, Durham, NC, (5)Section of Infectious Diseases, Durham Veteran's Affairs Medical Center, Durham, NC, (6)Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, NC, (7)Duke Clinical Research Institute, Durham, NC

Disclosures:

Q. Yan, None

S. Ahn, None

B. K. Sharma-Kuinkel, None

E. L. Tsalik, None

D. D. Cyr, None

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
NIAID: Research Contractor , Research support
DARPA: Grant Investigator , Research grant
Defense Threat Reduction Agency: Research Contractor , Research support
NIAID: Research Contractor , Research support

J. T. Thaden, None

R. Qi, None

M. Hu, None

F. Ruffin, None

E. Hecker, None

V. G. Fowler Jr., None

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