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

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.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Fine-scale genetic structure and gene dispersal in Centaurea corymbosa (Asteraceae) I. Pattern of pollen dispersal

Pollen dispersal was characterized within a population of the narrowly endemic perennial herb, Centaurea corymbosa, using exclusion-based and likelihood-based paternity analyses carried out on microsatellite data. Data were used to fit a model of pollen dispersal and to estimate the rates of pollen flow and mutation/genotyping error, by developing a new method. Selfing was rare (1.6%). Pollen dispersed isotropically around each flowering plant following a leptokurtic distribution, with 50% of mating pairs separated by less than 11 m, but 22% by more than 40 m. Estimates of pollen flow lacked precision (0-25%), partially because mutations and/or genotyping errors (0.03-1%) could also explain the occurrence of offspring without a compatible candidate father. However, the pollen pool that fertilized these offspring was little differentiated from the adults of the population whereas strongly differentiated from the other populations, suggesting that pollen flow rate among populations was low. Our results suggest that pollen dispersal is too extended to allow differentiation by local adaptation within a population. However, among populations, gene flow might be low enough for such processes to occur.FLWINinfo:eu-repo/semantics/publishe