Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis.
Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis.
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DOI：
10.4049/immunohorizons.2200007
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发表时间：
2022-02-11
期刊：
影响因子：
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通讯作者：
Frelinger, Jeffrey A
中科院分区：
文献类型：
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作者：
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
STAT 4在先天性和适应性免疫应答的产生中起关键作用。在没有STAT 4的情况下，Th 1应答，对真菌疾病的抗性至关重要，不会发生。在亚利桑那州和加州的地方病流行区，球孢子菌感染是社区获得性肺炎的主要原因。在某些人中，通常由于未知的原因，球虫感染导致血行播散和疾病进展，而不是典型的自限性肺炎。一个家族的三代成员患上了播散性球孢子菌病，促使进行遗传学调查。所有受影响的家族成员在STAT 4中具有单个杂合碱基变化，c.1877A>G，导致AA 626处的甘氨酸取代谷氨酸（STAT 4 E626 G/+）。一个敲入小鼠，杂合子的替代，发展更严重的实验球孢子菌病比野生型小鼠。抗CD 3/CD 28刺激后，Stat 4 E626 G/+ T细胞缺乏IFN-γ的产生。来自Stat 4 E626 G小鼠的脾细胞在体外显示出对IL-12/IL-18刺激的缺陷性应答。在体内，感染后早期，突变型Stat 4 E626 G/+小鼠不能在肺中产生IFN-γ和相关细胞因子，也不能在纵隔淋巴结中积累活化的适应性免疫细胞。因此，有缺陷的IFN γ诱导和STAT 4的适应性反应阻止了小鼠和人类球孢子菌病的正常控制。
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 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 STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/+). A knock-in mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than WT mice. Stat4E626G/+ T cells were deficient in production of IFN-gamma after anti-CD3/CD28 stimulation. Spleen cells from Stat4E626G mice showed defective responses to IL-12/IL-18 stimulation in vitro. In vivo, early after infection, mutant Stat4E626G/+ mice failed to produce IFN-gamma and related cytokines in the lung and to accumulate activated adaptive immune cells in mediastinal lymph nodes. Therefore, defective early induction of IFN gamma and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans.