Immunogenetics associated with severe coccidioidomycosis.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Hsu Amy P, Korzeniowska Agnieszka, Aguilar Cynthia C, Gu Jingwen, Karlins Eric, Oler Andrew J, Chen Gang, Reynoso Glennys V, Davis Joie, Chaput Alexandria, Peng Tao, Sun Ling, Lack Justin B, Bays Derek J, Stewart Ethan R, Waldman Sarah E, Powell Daniel A, Donovan Fariba M, Desai Jigar V, Pouladi Nima, Long Priel Debra A, Yamanaka Daisuke, Rosenzweig Sergio D, Niemela Julie E, Stoddard Jennifer, Freeman Alexandra F, Zerbe Christa S, Kuhns Douglas B, Lussier Yves A, Olivier Kenneth N, Boucher Richard C, Hickman Heather D, Frelinger Jeffrey, Fierer Joshua, Shubitz Lisa F, Leto Thomas L, Thompson George R, Galgiani John N, Lionakis Michail S, Holland Steven M
Аннотация
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.