Interleukin-12 Receptor 1 Deficiency Predisposing to Disseminated Coccidioidomycosis

Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 02/2011; 52(4):e99-e102. DOI: 10.1093/cid/ciq215
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    • "This current study expands on their work by clearly demonstrating that downstream ISGs are expressed to a greater extent in resistant DBA/2 compared to sensitive C57BL/6 mice (Figures 2 and 7) and that these genes are modulated by the JAK/STAT pathway (Figures 4 and 6), most likely activated by IFN-γ (Figure 7). These findings are highly relevant to human infection since patients with congenital deficiencies of IFN-γ and the interleukin 12 receptor beta 1 (IL-12rβ1) are susceptible to disseminated coccidioidomycosis [30,31]. "
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    ABSTRACT: BackgroundCoccidioidomycosis results from airborne infections caused by either Coccidioides immitis or C. posadasii. Both are pathogenic fungi that live in desert soil in the New World and can infect normal hosts, but most infections are self-limited. Disseminated infections occur in approximately 5% of cases and may prove fatal. Mouse models of the disease have identified strains that are resistant (e.g. DBA/2) or susceptible (e.g. C57BL/6) to these pathogens. However, the genetic and immunological basis for this difference has not been fully characterized.ResultsMicroarray technology was used to identify genes that were differentially expressed in lung tissue between resistant DBA/2 and sensitive C57BL/6 mice after infection with C. immitis. Differentially expressed genes were mapped onto biological pathways, gene ontologies, and protein interaction networks, which revealed that innate immune responses mediated by Type II interferon (i.e., IFNG) and the signal transducer and activator of transcription 1 (STAT1) contribute to the resistant phenotype. In addition, upregulation of hypoxia inducible factor 1A (HIF1A), possibly as part of a larger inflammatory response mediated by tumor necrosis factor alpha (TNFA), may also contribute to resistance. Microarray gene expression was confirmed by real-time quantitative PCR for a subset of 12 genes, which revealed that IFNG HIF1A and TNFA, among others, were significantly differentially expressed between the two strains at day 14 post-infection.ConclusionThese results confirm the finding that DBA/2 mice express more Type II interferon and interferon stimulated genes than genetically susceptible strains and suggest that differential expression of HIF1A may also play a role in protection.
    BMC Microbiology 09/2012; 12(1):218. DOI:10.1186/1471-2180-12-218 · 2.73 Impact Factor
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    ABSTRACT: Blastomycosis is a potentially fatal infection caused by Blastomyces dermatitidis, a fungus endemic to North America in areas surrounding the Ohio and Mississippi River valleys and the Great Lakes. The clinical manifestations, diagnostic techniques, and treatment strategies for blastomycosis are relatively well-described in the literature; however, the epidemiologic features of disease are not as clearly defined as those of other endemic mycoses, such as histoplasmosis and coccidioidomycosis. We review the ecologic and epidemiologic aspects of B. dermatitidis and blastomycosis, including geographic distribution, environmental niche, seasonality, and possible risk factors.
    Current Fungal Infection Reports 12/2012; 6(4). DOI:10.1007/s12281-012-0110-1
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    ABSTRACT: Delineating the infection susceptibility of primary immunodeficiencies allows insight into host immunity. Filamentous mold infections are seen most frequently in chronic granulomatous disease, a neutrophil disorder characterized by impaired superoxide production. Mucocutaneous candidiasis occurs in disorders of impaired interleukin (IL)-17 and IL-22 signaling, such as seen in autosomal dominant hyper-IgE (Job’s) syndrome and in disorders with autoantibodies to these cytokines. The endemic dimorphic fungi are in part controlled by disorders of the IL-12/interferon (IFN)-γ pathway, such as IFN-γ receptor and STAT1 defects. Understanding the pathways involved in these primary immunodeficiency disorders will also provide insight into these infections in secondary immunodeficiencies and allow guidance for novel therapies.
    Current Fungal Infection Reports 12/2011; 5(4). DOI:10.1007/s12281-011-0063-9
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