Role of human NK cells in the immune response to coccidioides

The National Institute of Allergy and Infectious Diseases awarded $712,977 to Northern California Institute For Research And Education, Inc. on September 3, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of human natural killer cells in immune response to Coccidioides.

The research maps coccidioides lung granulomas at single-cell resolution in patient specimens and models acute infection in human lung tissue explants to characterize early interactions between fungus, epithelial cells, and innate immune cells. The work defines coccidioides ligands and natural killer cell receptors implicated in fungal sensing and growth inhibition through human natural killer cell activation studies, receptor blocking and overexpression, and CRISPR/Cas9-generated coccidioides mutants defective in carbohydrate processing. The project conducts immune profiling across the spectrum of coccidioidomycosis disease to identify natural killer cell phenotypic correlates of severe or disseminated infection.

The period of performance runs through August 31, 2027, with work performed in San Francisco, California. The assistance type is a project grant.

Abstract

Coccidioides SPP., the causative agent of coccidioidomycosis, is a dimorphic environmental fungus found in the southwestern and western united states and in central and south america that can cause a range of infectious phenotypes in humans, ranging from asymptomatic pulmonary infection to life-threatening disseminated disease. The incidence and range of this pathogen are expanding, so the early (innate) immunological basis for differential host outcomes needs to be better understood. Innate immune cells, including natural killer (NK) cells, express germline-encoded receptors, some of which sense fungal cell wall carbohydrates. Coccidioides expresses carbohydrate structures during its complex dimorphic life cycle. In this katz R01 proposal, i will map at single cell resolution the coccidioides lung granuloma in patient specimens, then model acute coccidioides infection in human lung tissue explants to understand both the chronic granuloma and the earliest interactions between fungus, epithelial cells, and innate immune cells (aim 1). NK cells have been found to sense and inhibit the growth of several fungi, including coccidioides, and this project plans to define the implicated coccidioides ligands and NK cell receptors by studying human NK cell activation using a variety of coccidioides preparations; blocking, overexpressing, and knocking down NK receptors; and using crispr/CAS9 to generate coccidioides mutants defective in carbohydrate processing (aim 2). Finally, the proposed work involves conducting an immune profiling study of coccidioidomycosis patients across the spectrum of disease to identify NK cell phenotypic correlates of severe or disseminated coccidioidomycosis (aim 3). In understanding the NK response and host determinants of protection against coccidioides, this project will generate the information necessary to understand differential patient susceptibility to this fungus. IT will reveal tractable targets for augmenting the host response. For example, sugars, proteins, genes, or pathways essential for NK cell-mediated innate immunity to coccidioides could be targeted for enhanced function by small molecules or cellular infusions in exposed, infected, and immunocompromised patients. Finally, the approaches and results from this proposal will provide a roadmap to similar studies of other human pathogenic fungi.