42 - Common Population Variants Cause Susceptibility to Disseminated Coccidioidomycosis

Background: Coccidioides are endemic, dimorphic fungi found in soils of southwestern United States, Mexico and Central America. Infection occurs via inhalation of arthroconidia which swell, differentiate into spherules and rupture releasing endospores. While the majority of infected individuals will never report illness, roughly 1/3 seek medical attention for fungal pneumonia and ~1% of those present with disseminated coccidioidomycosis (DCM). IL12-IFNγ pathway mutations have been reported in DCM but are exceedingly rare and cannot account for the ~500-600 cases of DCM/year.

Methods: We performed whole exome sequencing on 66 individuals with DCM, retaining variants predicted damaging (CADD >15) with a population frequency < 10%.

Results: Homozygous CLEC7A c.714T >G; p.Y238* causing a truncated Dectin-1 receptor was overrepresented (OR=9.8449, 95% CI 3.0841 to 31.4260, P=0.0001). Dectin-1 signaling pathway variants included 3 homozygous and 11 heterozygous CLEC7A p.Y238* individuals, one each CLEC7A p.I223S and MALT1 p.R149Q and five PLCG2 p.R268W. Since Dectin-1 is the receptor for b-glucan, a major Coccidioides cell-wall component, we hypothesized that Dectin-1 pathway variants could affect fungal recognition and cellular response. Healthy control PBMCs stimulated with purified β-glucan or heat-killed Candida albicans induced 6-fold more TNFα than patients with homozygous or heterozygous CLEC7A, PLCG2 or MALT1 variants (P=0.0022, Ordinary one-way ANOVA). Additionally, one patient with a family history of DCM but lacking a defined mutation also failed to up-regulate TNFα after stimulation.Normalized TNF production from healthy control and DCM patient's peripheral blood mononuclear cells


Conclusion: These data are consonant with increased dissemination in Clec7a^-/- mice as well as in patients receiving anti-TNF biologics. These gene variants accounted for 31% of our DCM cohort (21/66 patients). This is the first demonstration of variants outside the IL12-IFNg pathway impairing fungal recognition and cellular response in coccidioidomycosis. Common heterozygous variants may be sufficient for disease susceptibility to highly pathogenic organisms.

Presenting Author(s)

• AH

  Amy P. Hsu

  Biologist / Student
  NIAID / NIH; University of Maryland, College Park
  Bethesda, MD

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

  Slides Slides and Audio

Co-Author(s)

• JD

  Joie Davis, AGN-BC

  Advanced Genetic Nurse, Board Certified
  Laboratory of Clinical Immunology and Microbiology
  Bethesda, Maryland

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• AC

  Alexandria L. Chaput, MS

  Research Specialist
  The University of Arizona
  Tucson, Arizona

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• DP

  Daniel A. Powell, PhD

  Assistant Research Specialist
  The University of Arizona
  Tucson, Arizona

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• NP

  Nima Pouladi, MD, PhD

  Computational Researcher
  The University of Arizona
  Tucson, Arizona

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• YL

  Yves Lussier, MD, FCAMI

  Director
  The University of Arizona
  Tucson, Arizona

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JF

  Joshua Fierer, MD

  Professor in Residence
  UC San Diego School of Medicine
  La Jolla, California

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JF

  Jeffrey A. Frelinger, PhD

  Professor
  University of Arizona
  Tucson, Arizona

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JG

  John N. Galgiani, MD

  Director
  The University of Arizona
  Tucson, Arizona

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• 

  Michail Lionakis, MD, ScD

  Chief, Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology
  National Institute of Allergy and Infectious Diseases
  Bethesda, Maryland

  Disclosure: Matinas BioPharma (Research Grant or Support)
• SH

  Steven M. Holland, MD

  Dr.
  Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
  Bethesda, Maryland

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.