ABSTRACT
BACKGROUND: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. OBJECTIVE: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. METHODS: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. RESULTS: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation. CONCLUSION: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.
Subject(s)
Coccidioidomycosis/genetics , Histoplasmosis/genetics , Mutation , STAT1 Transcription Factor/genetics , Adolescent , Adult , Cell Line, Transformed , Child , Coccidioidomycosis/diagnosis , Coccidioidomycosis/immunology , Cytokines/biosynthesis , Female , Gene Expression Regulation , Histoplasmosis/diagnosis , Histoplasmosis/immunology , Humans , Male , Phosphorylation , Protein Inhibitors of Activated STAT/metabolism , STAT1 Transcription Factor/metabolism , Th17 Cells/immunology , Transcriptional Activation , Young AdultABSTRACT
BACKGROUND: This study was conducted to identify clinical factors associated with development of infection caused by methicillin-resistant Staphylococcus aureus (MRSA) among hospitalized patients with nasal MRSA colonization. METHODS: We conducted a prospective cohort with nested case-control study at a 672-bed, public, academic hospital in Dallas, Texas. The study duration was from January 1, 2008, to July 28, 2009. From the cohort of patients who had presence of nasal colonization with MRSA at admission, we identified patients who developed subsequent infection with MRSA during a 3-month period. We compared these patients (cases) with colonized patients who remained uninfected (controls; 2 controls per case). We collected demographic and clinical data and performed statistical analyses. RESULTS: During the 19-month study period, 426 patients were found to have nasal colonization with MRSA. Of these, 36 (8.5%) developed a subsequent infection with MRSA within 3 months. When these 36 cases were compared with 72 controls, the factors independently associated with the development of subsequent infection were development of pressure ulcer during hospital stay (adjusted odds ratio, 5.82; 95% confidence interval: 2.21-15.31; P value=.000) and preadmission steroid therapy (adjusted odds ratio, 13.2; 95% confidence interval: 2.44-70.97; P value=.003). CONCLUSION: History of steroid therapy prior to admission and development of pressure ulcer are associated with increased risk of subsequent MRSA infection in patients nasally colonized with MRSA.