Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis

Abstract

STAT4 plays a critical role in the generation of both innate and adaptive immune responses. In the absence of STAT4, Th1 responses, critical for resistance to fungal disease, do not occur. Infection with the dimorphic fungus, Coccidioides, is amajor cause of community-acquired pneumonia in the endemic regions of Arizona and California. In some people and often for unknown reasons, coccidioidal infection results in hematogenous dissemination and progressive disease rather than the typical self-limited pneumonia. Members of three generations in a family developed disseminated coccidioidomycosis, prompting genetic investigation. All affected family members had a single heterozygous base change in STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/1). A knockinmouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-typemice. Stat4E626G/1 T cells were deficient in production of IFN-γ after anti-CD3/CD28 stimulation. Spleen cells fromStat4E626G mice showed defective responses to IL-12/IL-18 stimulation in vitro. In vivo, early postinfection, mutant Stat4E626G/1 mice failed to produce IFN-γ and related cytokines in the lung and to accumulate activated adaptive immune cells inmediastinal lymph nodes. Therefore, defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in bothmice and humans. © 2022 The Authors.