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Published on: February 9, 2011
Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis
Qin Yan1, Batu K Sharma-Kuinkel1, Hitesh Deshmukh2
1Division of Infectious Diseases & International Health, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
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.
Insights
Researchers identified two genes, Dusp3 and Psme3, that increase susceptibility to Staphylococcus aureus infections in mice and humans. Lower levels of these genes correlate with higher infection risk and inflammation.
Area of Science:
- Genetics
- Immunology
- Microbiology
Background:
- Staphylococcus aureus (S. aureus) infections pose a significant health threat, with genetic factors influencing host susceptibility.
- Identifying genetic determinants of S. aureus infection susceptibility is crucial for understanding disease pathogenesis.
Purpose of the Study:
- To identify and functionally characterize genetic factors contributing to S. aureus infection susceptibility in A/J mice.
- To investigate the role of identified genes in human S. aureus infections.
Main Methods:
- Quantitative trait loci (QTL) mapping in A/J mice to identify susceptibility regions.
- Whole genome transcription profiling and quantitative PCR (qPCR) to identify differentially expressed genes.
- siRNA-mediated gene knockdown and stimulation assays in macrophage cell lines (RAW264.7 and BMDMs).
Main Results:
- A significant QTL region on chromosome 11 was associated with S. aureus susceptibility.
- Five genes (Dcaf7, Dusp3, Fam134c, Psme3, Slc4a1) were differentially expressed in susceptible mice and humans.
- Dusp3 and Psme3 were down-regulated in susceptible mice and their knockdown increased cytokine production via NF-κB signaling.
- Macrophages from mice with an A/J chromosome 11 segment showed increased cytokine production and NF-κB activity.
Conclusions:
- Dusp3 and Psme3 are key genetic contributors to S. aureus infection susceptibility in A/J mice.
- These genes play a role in the inflammatory response to S. aureus infection and may be relevant in human infections.
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