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

• Published in: ImmunoHorizons 2022-02, Vol.6 (2), p.130-143
• Main Authors: Powell, Daniel A, Hsu, Amy P, Shubitz, Lisa F, Butkiewicz, Christine D, Moale, Hilary, Trinh, Hien T, Doetschman, Thomas, Georgieva, Teodora G, Reinartz, Dakota M, Wilson, Justin E, Orbach, Marc J, Holland, Steven M, Galgiani, John N, Frelinger, Jeffrey A
• Format: Article
• Language: English
• Subjects: Animals; Coccidioidomycosis - genetics; Genetic Predisposition to Disease; Humans; Mice; Mice, Inbred BALB C; Mice, Knockout; Point Mutation; STAT4 Transcription Factor - genetics
• ISSN: 2573-7732; 2573-7732
• DOI: 10.4049/immunohorizons.2200007

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, , is a major 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 , c.1877A>G, causing substitution of glycine for glutamate at AA626 ( ). A knockin mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-type mice. T cells were deficient in production of IFN-γ after anti-CD3/CD28 stimulation. Spleen cells from mice showed defective responses to IL-12/IL-18 stimulation in vitro. In vivo, early postinfection, mutant mice failed to produce IFN-γ and related cytokines in the lung and to accumulate activated adaptive immune cells in mediastinal lymph nodes. Therefore, defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans.