TY - JOUR
T1 - Dusp3 and Psme3 Are Associated with Murine Susceptibility to Staphylococcus aureus Infection and Human Sepsis
AU - Yan, Qin
AU - Sharma-Kuinkel, Batu K.
AU - Deshmukh, Hitesh
AU - Tsalik, Ephraim L.
AU - Cyr, Derek D.
AU - Lucas, Joseph
AU - Woods, Christopher W.
AU - Scott, William K.
AU - Sempowski, Gregory D.
AU - Thaden, Joshua
AU - Rude, Thomas H.
AU - Ahn, Sun Hee
AU - Fowler, Vance G.
N1 - Funding Information:
VGF served as Chair of V710 Scientific Advisory Committee (Merck), has received grant support from Cerexa, Pfizer, Advanced Liquid Logic, MedImmune, has been a paid consultant for Merck, Astellas, Affinium, Bayer, Theravance, Cubist, Cerexa, Durata, Pfizer, NovaDigm, Novartis, Medicines Company, Biosynexus, MedImmune, and Inimex, and has received honoraria from Merck, Astellas, Cubist, Pfizer, Theravance, and Novartis. JL is employed by Quintiles Innovations. This does not alter our adherence to all PLOS policies on sharing data and materials.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1004149
DO - 10.1371/journal.ppat.1004149
M3 - Article
C2 - 24901344
AN - SCOPUS:84903464217
VL - 10
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 6
M1 - e1004149
ER -