Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2
Articolo
Data di Pubblicazione:
2026
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.
Tipologia CRIS:
1.1 Articolo in rivista
Keywords:
COVID-19; inborn errors of immunity; interferon; mitocholdrial DNA; RNA polymerase III
Elenco autori:
Mohlenberg, M.; Jorgensen, S. E.; Van Der Sluis, R. M.; Zillinger, T.; Hinke, D. M.; Hollensen, A. K.; Hansen, A. L.; Hausfater, P.; Gorochov, G.; Tubach, F.; Ghosn, J.; Laouenan, C.; Storgaard, M.; Holm, C. K.; Su, H.; De Diego, R. P.; Pujol, A.; Zhang, S. -Y.; Zhang, Q.; Vianna, F. S. L.; Abel, L.; Cobat, A.; Casanova, J. -L.; Mogensen, T. H.; Aiuti, A.; Al-Muhsen, S.; Al-Mulla, F.; Anderson, M. S.; Andreakos, E.; Arias, A. A.; Arkin, L. M.; Feldman, H. B.; Bastard, P.; Belot, A.; Biggs, C. M.; Bogunovic, D.; Bolze, A.; Bondarenko, A.; Borghesi, A.; Bousfiha, A. A.; Brodin, P.; Bryceson, Y.; Casanova, J. -L.; Casari, G.; Christodoulou, J.; Cobat, A.; Colo-Bran, R.; Condino-Neto, A.; Constantinescu, S. N.; Cooper, M. A.; Dalgard, C. L.; Desai, M.; Drolet, B. A.; Dundar, M.; Duval, X.; Duvlis, S.; El Baghdadi, J.; Eloy, P.; Espinosa-Padilla, S.; Fellay, J.; Flores, C.; Franco, J. L.; Froidure, A.; Gorochov, G.; Gut, M.; Haerynck, F.; Hagin, D.; Halwani, R.; Hammarstrom, L.; Heath, J. R.; Hsieh, E. W. Y.; Husebye, E.; Imai, K.; Itan, Y.; Jouanguy, E.; Kaja, E.; Karamitros, T.; Kisand, K.; Ku, C. -L.; Lau, Y. -L.; Ling, Y.; Lucas, C. L.; Mahevas, M.; Mansouri, D.; Marodi, L.; Mentre, F.; Meyts, I.; Milner, J. D.; Mironska, K.; Mogensen, T. H.; Morio, T.; Ng, L. F. P.; Notarangelo, L. D.; Novelli, A.; Novelli, G.; O'Farrelly, C.; Okada, S.; Okamoto, K.; Ozcelik, T.; Ozcelik, F.; Pan-Hammarstrom, Q.; De Diego, R. P.; Perez-Tur, J.; Perlin, D. S.; Peter, J.; Planas, A. M.; Prando, C.; Pujol, A.; Puel, A.; Quintana-Murci, L.; Ramaswamy, S.; Renia, L.; Resnick, I.; Rodriguez-Gallego, C.; Sancho-Shimizu, V.; Sediva, A.; Seppanen, M. R. J.; Shahrooei, M.; Shcherbina, A.; Slaby, O.; Snow, A. L.; Soler-Palacin, P.; Soumelis, V.; Spaan, A. N.; Su, H. C.; Tancevski, I.; Tangye, S. G.; Tayoun, A. A.; Temel, S. G.; Thorball, C.; Tiberghien, P.; Trouillet-Assant, S.; Turvey, S. E.; Furkan Uddin, K. M.; Uddin, M. J.; Van De Beek, D.; Vianna, F. S. L.; Vinh, D. C.; Von Bernuth, H.; Wauters, J.; Zatz, M.; Zhang, Q.; Zhang, S. -Y.; Benfield, T.; Bodilsen, J.; Hansen, K. S.; Helleberg, M.; Storgaard, M.; Pereira, A.; De Oliveira Fam, B. S.; Sgarioni, E.; Rodrigues, G. M.; Giudicelli, G. C.; Nunes, K.; Pereira, L. V.; Rodrigues, M. R.; Feira, M. F.; Castro E Silva, M. A.; Wissmann, M. S.; Prado, M. J.; Cadore, N. A.; Lemes, R. B.; Sbruzzi, R. C.; Artigalas, O.; Hunemeier, T.; Bureau, S.; Vacher, Y.; Gysembergh-Houal, A.; Demerville, L.; Benleulmi-Chaachoua, A.; Abad, S.; Abassi, R.; Abdellaoui, A.; Abdelmalek, A.; Abdoul, H.; Abergel, H.; Abeud, F.; Abgrall, S.; Abisror, N.; Adechian, M.; Aderdour, N.; Admane, H. F.; Adnet, F.; Afritt, S.; Agostini, H.; Aguilar, C.; Agut, S.; Aiello, T. F.; Kaci, M. A.; Oufella, H. A.; Ajeenthiravasan, G.; Alauzy, V.; Alby-Laurent, F.; Allard, L.; Alyanakian, M. -A.; Borrero, B. A.; Amam, S.; Amrouche, L.; Andronikof, M.; Anglicheau, D.; Anguel, N.; Annane, D.; Aounzou, M.; Aparicio, C.; Aratus, G.; Arlet, J. -B.; Arzoine, J.; Aslangul, E.; Assefi, M.; Aubry, A.; Audiffred, L.; Audureau, E.; Auger, C. N.; Auregan, J. -C.; Awotar, C.; Milla, S. A.; Azan, D.; Azemar, L.; Azzouguen, B.; Elrufaai, M. B.; Badsi, A.; Bakouboula, P.; Balcerowiak, C.; Balde, F.; Baldivia, E.; Bangamingo, E. -F.; Baptiste, A.; Baran-Marszak, F.; Barau, C.; Barget, N.; Baronnet, F.; Barthelemy, R.; Baudel, J. -L.; Baudry, C.; Baudry, E.; Beaugerie, L.; Belamri, A.; Belaube, N.; Belilita, R.; Bellassen, P.; Belmokhtar, R.; Beltran, I.; Benainous, R.; Benallaoua, M.; Benamouzig, R.; Benbara, A.; Benhida, J.; Benkhelouf, A.; Benlagha, J.; Benmostafa, C.; Benothmane, S.; Bentifraouine, M.; Berard, L.; Bernier, Q.; Berti, E.; Bertier, A.; Berton, L.; Bessis, S.; Beurton, A.; Bianco, C.; Bianquis, C.; Bidar, F.; Blanche, P.; Blayau, C.; Bleibtreu, A.; Blin, E.; Bloch-Queyrat, C.; Boissier, M. -C.; Bollens, D.; Bolzoni, M.; Bompard, R. P.; Bonnet, N.; Bonnouvrier, J.; Botha, S.; Boucenna, W.; Bouchama, F.; Bouchaud, O.; Bouchghoul, H.; Boudjebla, T
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