Factors regulated by interferon gamma and hypoxia-inducible factor 1A contribute to responses that protect mice from Coccidioides immitis infection

Abstract

Doc number: 218

Abstract

Background: Coccidioidomycosis 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.

Results: Microarray 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.

Conclusion: These 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.