title: Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis.
abstract: Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus -infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Batu K
authors.initials: BK
authors.lastname: Sharma-Kuinkel
authors.affiliation: Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Deshmukh
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America; Emergency Medicine Service, Durham Veteran's Affairs Medical Center, Durham, North Carolina, United States of America; Duke Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America.
authors.forename: Ephraim L
authors.initials: EL
authors.lastname: Tsalik
authors.affiliation: Duke Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Cyr
authors.affiliation: Quintiles Innovations, Morrisville, North Carolina, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America; Duke Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America; Section on Infectious Diseases, Durham Veteran's Affairs Medical Center, Durham, North Carolina, United States of America.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Woods
authors.affiliation: Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.affiliation: Duke Human Vaccine Institute, Durham, North Carolina, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Thaden
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America; Duke Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America; Duke Clinical Research Institute, Durham, North Carolina, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Thaden
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rude
authors.affiliation: Department of Biochemistry School of Dentistry, Chonnam National University, Bukgu, Gwangju, Korea.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America; Duke Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, United States of America; Duke Clinical Research Institute, Durham, North Carolina, United States of America.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016470:Bacteremia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004198:Disease Susceptibility; D054640:Dual Specificity Phosphatase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013203:Staphylococcal Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D011994:Recombinant Proteins; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; C517026:Dusp3 protein, mouse; D046988:Proteasome Endopeptidase Complex