Journal article
MICBG406A polymorphism reduces risk of mechanical ventilation and death during viral acute lung injury
JCI insight, v 10(15)
03 Jul 2025
PMID: 40608426
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
MICB is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from the IMPACC cohort. Associations between MICBG406A and outcomes were determined by linear regression or Cox Proportional Hazards models. We also measured immune profiles of peripheral blood, upper and lower airway. We identified 560 major allele homozygous patients, and 426 and 50 with one or two copies of the variant allele. MICBG406A conferred reduced odds of severe COVID-19 (OR = 0.73, CI = 0.58-0.93, P = 0.04). MICBG406A homozygous participants demonstrated 34% reduced cumulative odds for mechanical ventilation or death (CI = 0.51-0.85, P = 0.005) and 43% reduced risk for mortality (CI = 0.35-0.77, P = 0.001). Patients with MICBG406A variant alleles had reduced soluble inflammatory mediators and differential regulation of multiple immune pathways. These findings demonstrate a novel association between increasing MICBG406A variant allele copies and reduced COVID-19 severity, independent of SARS-CoV-2 viral burden and humoral immunity, suggesting the NKG2D-ligand pathway as an intervention target.
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Details
- Title
- MICBG406A polymorphism reduces risk of mechanical ventilation and death during viral acute lung injury
- Creators
- Harry Pickering - University of California, Los AngelesNarges Alipanah-Lechner - Department of Medicine, UCSF, San Francisco, United States of AmericaErnie Chen - Yale UniversityDylan Duchen - Yale UniversityHolden T Maecker - Stanford UniversitySeunghee Kim-Schulze - Icahn School of Medicine at Mount SinaiRuth R Montgomery - Yale UniversityChris Cotsapas - Yale UniversityHanno Steen - Boston Children's HospitalFlorian Krammer - Icahn School of Medicine at Mount SinaiCharles R Langelier - Department of Medicine, UCSF, San Francisco, United States of AmericaOfer Levy - Boston Children's HospitalLindsey R Baden - Brigham and Women's HospitalEsther Melamed - The University of Texas at AustinLauren Ir Ehrlich - The University of Texas at AustinGrace A McComsey - University Hospitals of ClevelandRafick P Sekaly - Case Western Reserve UniversityCharles B Cairns - Drexel UniversityElias K Haddad - Drexel UniversityAlbert C Shaw - Yale UniversityDavid A Hafler - Yale UniversityDavid B Corry - Baylor College of MedicineFarrah Kheradmand - Baylor College of MedicineMark A Atkinson - University of FloridaScott C Brakenridge - University of FloridaNelson I Agudelo Higuita - OU HealthJordan P Metcalf - University of Oklahoma Health Sciences CenterCatherine L Hough - Oregon Health & Science UniversityWilliam B Messer - Oregon Health & Science UniversityBali Pulendran - Stanford UniversityKari C Nadeau - Stanford UniversityMark M Davis - Stanford UniversityAna Fernandez-Sesma - Icahn School of Medicine at Mount SinaiViviana Simon - Icahn School of Medicine at Mount SinaiMonica Kraft - University of ArizonaChristian Bime - University of ArizonaDavid J Erle - Department of Medicine, UCSF, San Francisco, United States of AmericaJoanna Schaenman - University of California, Los AngelesAl Ozonoff - Boston Children's HospitalBjoern Peters - La Jolla Institute for ImmunologySteven H Kleinstein - Yale UniversityAlison D Augustine - National Institute of Allergy and Infectious DiseasesJoann Diray-Arce - Yale UniversityPatrice M Becker - National Institute of Allergy and Infectious DiseasesNadine Rouphael - Emory UniversityMatthew C Altman - University of WashingtonSteven E Bosinger - Emory UniversityWalter L Eckalbar - Department of Medicine, UCSF, San Francisco, United States of AmericaImpacc Network - Boston UniversityCarolyn S Calfee - Department of Medicine, UCSF, San Francisco, United States of AmericaOscar A Aguilar - University of California, San FranciscoElaine F Reed - University of California, Los AngelesJohn R Greenland - Department of Medicine, UCSF, San Francisco, United States of AmericaDaniel R Calabrese - Department of Medicine, UCSF, San Francisco, United States of America
- Publication Details
- JCI insight, v 10(15)
- Publisher
- American Society for Clinical Investigation
- Number of pages
- 18
- Grant note
- Cystic Fibrosis Foundation: CALABR19Q0 Biomedical Laboratory Research and DevelopmentVA Office of Research and Development grant: BX005301 Burroughs Wellcome FundCancer Research Institute FellowParker Institute for Cancer ImmunotherapyNIH: AI068129 IMPACCNetwork: NIH: 5T32DA018926-18 NIAID, NIH: 3U19AI1289130, U19AI128913-04S1, R01AI122220 NCATS, NIH: UM1TR004528 National Science Foundation: DMS2310836
We thank the participants of the study for their voluntary enrollment and contribution of samples for this work. See Supplemental Acknowledgments for consortium details. We acknowledge the assistance of the following individuals: Sanya Thomas, Mitchell Cooney, Shun Rao, Sofia Vignolo, and Elena Morrocchi (all from the CDCC) ; Arash Naeim, Marianne Bernardo, Sarahmay Sanchez, Shannon Intluxay, Clara Magyar, Jenny Brook, Estefania Ramires-Sanchez, Megan Llamas, Claudia Perdomo, Clara E. Magyar, and Jennifer A. Fulcher (all from the David Geffen School of Medicine at UCLA) ; members of the UCLA Center for Pathology Research Services and the Pathology Research Portal; and M. Catherine Muenker, Dimitri Duvilaire, Maxine Kuang, William Ruff, Khadir Raddassi, Denise Shepherd, Haowei Wang, Omkar Chaudhary, Syim Salahuddin, John Fournier, Michael Rainone, and Maxine Kuang (all from the Yale School of Medicine) . We thank the leadership of Boston Children's Hospital including Wendy Chung, Gary Fleisher, and Kevin Churchwell for their support for the Precision Vaccines Program. ADD's and PMB's coauthorship of this report does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the NIH, or any other agency of the United States Government. This work was supported by Cystic Fibrosis Foundation grant CALABR19Q0 and Biomedical Laboratory Research and Development, VA Office of Research and Development grant BX005301 (DRC); Burroughs Wellcome Fund, Cancer Research Institute Fellow (OAA); the Parker Institute for Cancer Immunotherapy and NIH grant AI068129 (OAA). NIHR351HL140026 (CSC). IMPACCNetwork: NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17,5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and NCATS, NIH UM1TR004528 and National Science Foundation (DMS2310836) .
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Emergency Medicine
- Web of Science ID
- WOS:001546989300001
- Scopus ID
- 2-s2.0-105013260017
- Other Identifier
- 991022062981604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental