PDF(Pubmed)
Abstract：
Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.
摘要：
播散性球虫病（DCM）是由球虫引起的，美国西南部和墨西哥特有的病原真菌。大约30％的感染者患病，不到1%的人发展为播散性疾病。为了解决为什么有些人允许传播，我们招募了DCM患者,并进行了全外显子组测序.在一组67例DCM患者的探索性研究中，2个有单倍体不足的STAT3突变，67例中有34例存在β-葡聚糖感应和反应缺陷。与健康对照相比,损害CLEC7A和PLCG2变体与来自PBMC的β-葡聚糖刺激的TNF-α的产生受损相关。使用祖先匹配的控件，损伤性CLEC7A和PLCG2变异体在DCM中过度表现，包括CLEC7AY238*和PLCG2R268W。111例DCM患者的验证队列证实了PLCG2R268W，CLEC7AI223S,和CLEC7AY238*变体。用DECTIN-1激动剂刺激在转染的细胞中诱导DUOX1/DUOXA1衍生的过氧化氢[H2O2]。在发现和验证队列中，杂合的DUOX1或DUOXA1变体损害了H2O2的产生。患有DCM的患者具有影响TNF-α和H2O2产生的β-葡聚糖感觉或反应受损。球虫识别受损和细胞反应降低与播散性球虫菌病相关。
