Host Immunogenetics and Fungal Virulence Mechanisms in Coccidioidomycosis

There is a broad heterogeneity of clinical outcomes after infection with Coccidioides (Cocci) ranging from
asymptomatic infection to mild pulmonary disease (“Valley fever”) to a life-threatening, invasive disease called
disseminated coccidioidomycosis (DCM). Everyone in the endemic areas is susceptible to this infection, but we
have almost no ability to predict who will develop disseminated disease and lack an understanding of why they
do so. With nearly 10K reported cases of Valley fever and 200 cases of DCM yearly in California, our state alone
spends ~$1B yearly on coccidioidomycosis. Thus, there is an urgent need to better understand DCM to enable
better prevention, diagnostics, prognostics, and treatments. Our team's long-term goal is to study the
intersection between the virulence programs of Coccidioides spp that maliciously exploit defective immunity, and
the dysregulation of genetic and immunological programs of innate and adaptive immunity that allow for severe
disease to take hold.
Our program will bring together a cohesive and multi-disciplinary team of immunologists, geneticists,
computational biologists, fungal microbiologists, and clinicians. Combining deep expertise with synergistic goals
will enable breakthroughs.
Our consortium includes four Projects and three supporting Cores: Project 1 addresses the innate immune
responses to cocci infection that go awry in the first stages of cocci infection; Project 2 addresses the adaptive
immune responses to cocci infection that go awry in protecting the host from disseminated disease; Project 3
addresses the genomic basis of cocci disease, from common variants that underlie susceptibility due to ancestry
to rare variants that disable host defenses; and Project 4 addresses the contributions of fungal virulence factors
in enabling the organisms to evade host immune defenses in some individuals. Our program includes an
Administrative Core (Core A) that facilitates communications between investigators, organizes meetings and
finances, and runs the Developmental Research Program. We also propose a unified Clinical Samples Core
(Core B) comprising two of the largest coccidioidomycosis clinics in California, and a Model Organisms Core
(Core C) that will carry out all experiments requiring BSL3 safety measures. These Cores together empower the
proposed projects by providing common reagents, human samples, tools, and expertise.
Our proposed investigations have the potential to transform our understanding of invasive fungal infections
and will restore hope for patients through new approaches to prevent, diagnose, and treat DCM.

Grant Number: 5U19AI166059-04
NIH Institute/Center: NIH
Principal Investigator: MANISH BUTTE