Amy P. Hsu, United States of America
National Institutes of Health, National Institute of Allergy and Infectious Diseases Laboratory of Clinical Immunology and MicrobiologyPresenter of 1 Presentation
GENETIC ANALYSIS OF DISSEMINATED COCCIDIOIDOMYCOSIS
Abstract
Background and Aims
Coccidioides spp are pathogenic, dimorphic fungi endemic in the desert soils of the Southwestern United States. While 2/3 of those infected never come to medical attention, ~1/3 develop protracted pneumonia; less than 1% of those infected disseminate. Epidemiologic studies have demonstrated increased dissemination rates among individuals of African-American, Hispanic and Filipino descent suggesting underlying genetic susceptibility. Previously we identified causative IFNGR1, IL12RB1, STAT1 and STAT3 mutations in multiple disseminated coccidioidomycosis patients (DCM), highlighting the IFNG-IL12/23 pathway as crucial to control infection.
Methods
To expand on these findings, whole exome sequencing was performed on 49 DCM and 44 contained-pulmonary patients (pCocci).
Results
DCM had more variants with population frequency less than 10% than pCocci (p=0.0345). Comparing individual gene burdens in DCM and pCocci, we identified 310 genes significantly increased in DCM, including a subset related to iron homeostasis. Targeted gene list analysis of macrophage response genes, IFNG-IL12/23 pathway, IL17 and Dectin-1 signaling and iron homeostasis (359 genes) found more variants in DCM than pCocci patients (p=0.0122) and DCM patients had a higher burden of deleterious (CADD>20) variants than pCocci (p<0.0001). Further, patterns appear in DCM specific gene sets such as STATs, IL12, IL17 or Dectin-1 signaling, suggesting that these pathways affect dissemination. In DCM variants STAT3 (p.V461L) and DECTIN-1 (p.R238*) were over-represented compared to ExAC.
Conclusions
In conclusion, WES demonstrated distinct genetic burdens in DCM vs pCocci, implicating innate immune pathways as well as iron homeostasis. These data deepen our understanding of risk factors of disseminated coccidioidomycosis.