Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2
Abstract
The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection ranges from asymptomatic cases to critical COVID-19 pneumonia. To investigate the role of host genetics in susceptibility to critical COVID-19 and identify pathophysiological mechanisms and pathways, we analyzed whole-exome and whole-genome sequencing data from the COVID Human Genetic Effort. We identified 10 rare, monoallelic predicted loss-of-function variants in 18 patients in POLR3A and POLR3C encoding two subunits of RNA polymerase III (POL III), a nuclear multisubunit enzyme, which has been implicated in cytosolic DNA sensing. These variants were deleterious for expression of full-length POLR3A and POLR3C proteins. We demonstrate that human pulmonary A549-hACE2 cells with reduced POLR3A or POLR3C expression exhibit impaired type I IFN responses to transfected mitochondrial DNA (mtDNA) or SARS-CoV-2 infection, together with increased viral replication. Mechanistically, we show that SARS-CoV-2 induces cellular mtDNA release via oligomerization of the mitochondrial voltage-dependent anion channel under virus-induced oxidative stress, enabling POL III–mtDNA interaction. These findings establish POL III as a sensor of endogenous mtDNA released during viral infection and indicate that autosomal dominant POL III haploinsufficiency may predispose individuals to critical COVID-19.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Michelle Møhlenberg
Department of Biomedicine, Aarhus University
Sofie Eg Jørgensen
Department of Biomedicine, Aarhus University
Renée Marije van der Sluis
Department of Biomedicine, Aarhus University
Thomas Zillinger
Department of Biomedicine, Aarhus University
Daniëla Maria Hinke
Department of Biomedicine, Aarhus University
Anne Kruse Hollensen
Department of Biomedicine, Aarhus University
Anne Louise Hansen
Department of Biomedicine, Aarhus University
Pierre Hausfater
Pitie Salpetriere Hospital, Departement de Sante Publique and Sorbonne University, INSERM, Institut Pierre Louis d‘Epidemiologie et de Sante Publique
Guy Gorochov
Pitie Salpetriere Hospital, Departement de Sante Publique and Sorbonne University, INSERM, Institut Pierre Louis d‘Epidemiologie et de Sante Publique
Florence Tubach
Pitie Salpetriere Hospital, Departement de Sante Publique and Sorbonne University, INSERM, Institut Pierre Louis d‘Epidemiologie et de Sante Publique
Jade Ghosn
Assistance Publique–Hôpitaux de Paris.Nord, Hopital Bichat-Claude Bernard, Service des Maladies Infectieuses, Paris F75018, France and Universite Paris Cite, INSERM UMR 1137 IAME
Cedric Laouenan
Assistance Publique–Hôpitaux de Paris.Nord, Hopital Bichat-Claude Bernard, Service des Maladies Infectieuses, Paris F75018, France and Universite Paris Cite, INSERM UMR 1137 IAME
Merete Storgaard
Department of Infectious Diseases, Aarhus University Hospital
Christian Kanstrup Holm
Department of Biomedicine, Aarhus University
Helen Su
National Institute of Allergy and Infectious Diseases, NIH
Rebeca Pérez de Diego
Institute of Biomedical Research of IdiPAZ, University Hospital “La Paz”
Aurora Pujol
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L’Hospitalet de Llobregat
Shen-Ying Zhang
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University
Qian Zhang
Fernanda Sales Luiz Vianna
Genomic Medicine, Experimental Research Center, Hospital de Clínicas de Porto Alegre
Laurent Abel
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University
Aurélie Cobat
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University
Jean-Laurent Casanova
Trine H. Mogensen
Department of Biomedicine, Aarhus University