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Dissecting genetics allowing dissemination of Coccidioides spp. infections

Wednesday, September 14, 2016 — Poster Session I

3:00 p.m. – 4:30 p.m.
FAES Terrace
NIAID
GEN-16

Authors

  • AP Hsu
  • JN Galgiani
  • SM Holland

Abstract

The highly pathogenic Coccidioides spp are dimorphic fungi endemic to the deserts of the Southwestern US and Mexico infecting hosts after inhalation. Annually, 3% of exposed individuals are infected, the majority rarely coming to medical attention. Approximately 1/3 of those infected develop severe pulmonary disease, clearing over 5-6 months, while 1% develop disseminated coccidioidomycosis (DCM). African-Americans have an 8-10X higher rate of DCM suggesting a genetic basis for susceptibility to dissemination. Previously reported DCM associated monogenic defects include biallelic mutations in IL12RB1 and IFNGR1 as well as dominant missense mutations in STAT1, leading to impaired IFNγ/IL12 signaling. We screened 36 DCM patients using next-generation sequencing, filtering for rare, deleterious variants. We identified a novel, heterozygous mutation in STAT4, (c.1877 A>G; p.E626G) in a 3 generation DCM pedigree and a novel, homozygous, nonsense mutation in IL12RB1 (c.1623_24GC>TT, p.Q542X) in an unrelated patient. Additional, heterozygous deleterious variants were identified broadly falling into three categories, 1)innate immune sensing, (DDX58(RIG-1), IFIH1(MDA5), TMEM173(STING)); 2)downstream signaling (IRF5, RIPK2, IKBKB); 3)proteins involved in IL12/IFNγ signaling (IL12RB2). Compared to isolated pulmonary patients, DCM patients have decreased in vitro IFNγ production in response to cocci antigen. Our data suggest cocci antigen signals through discrete pathways and heterozygous variants may dampen the host’s ability to control infection, allowing dissemination. These data may serve as a model to interrogate genetic variations in disseminated disease from other highly pathogenic organisms such as Mycobacterium tuberculosis. The DCM dataset is being compared to patients with contained pulmonary coccidioidomycosis to further narrow dissemination related variants.

Category: Genetics and Genomics