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Defective Rna Polymerase Iii Sensing of Mitochondrial Dna in Pulmonary Epithelial Cells Impairs Type I Ifn Immunity to Sars-Cov-2 Publisher Pubmed



Mohlenberg M ; Jorgensen SE ; Van Der Sluis RM ; Zillinger T ; Hinke DM ; Hollensen AK ; Hansen AL ; Hausfater P ; Gorochov G ; Tubach F ; Ghosn J ; Laouenan C ; Storgaard M ; Holm CK Show All Authors
Authors
  1. Mohlenberg M
  2. Jorgensen SE
  3. Van Der Sluis RM
  4. Zillinger T
  5. Hinke DM
  6. Hollensen AK
  7. Hansen AL
  8. Hausfater P
  9. Gorochov G
  10. Tubach F
  11. Ghosn J
  12. Laouenan C
  13. Storgaard M
  14. Holm CK
  15. Su H
  16. De Diego RP
  17. Pujol A
  18. Zhang SY
  19. Zhang Q
  20. Vianna FSL
  21. Abel L
  22. Cobat A
  23. Casanova JL
  24. Mogensen TH
  25. Aiuti A
  26. Almuhsen S
  27. Almulla F
  28. Anderson MS
  29. Andreakos E
  30. Arias AA
  31. Arkin LM
  32. Feldman HB
  33. Bastard P
  34. Belot A
  35. Biggs CM
  36. Bogunovic D
  37. Bolze A
  38. Bondarenko A
  39. Borghesi A
  40. Bousfiha AA
  41. Brodin P
  42. Bryceson Y
  43. Casanova JL
  44. Casari G
  45. Christodoulou J
  46. Cobat A
  47. Colobran R
  48. Condinoneto A
  49. Constantinescu SN
  50. Cooper MA
  51. Dalgard CL
  52. Desai M
  53. Drolet BA
  54. Dundar M
  55. Duval X
  56. Duvlis S
  57. El Baghdadi J
  58. Eloy P
  59. Espinosapadilla S
  60. Fellay J
  61. Flores C
  62. Franco JL
  63. Froidure A
  64. Gorochov G
  65. Gut M
  66. Haerynck F
  67. Hagin D
  68. Halwani R
  69. Hammarstrom L
  70. Heath JR
  71. Hsieh EWY
  72. Husebye E
  73. Imai K
  74. Itan Y
  75. Jouanguy E
  76. Kaja E
  77. Karamitros T
  78. Kisand K
  79. Ku CL
  80. Lau YL
  81. Ling Y
  82. Lucas CL
  83. Mahevas M
  84. Mansouri D
  85. Marodi L
  86. Mentre F
  87. Meyts I
  88. Milner JD
  89. Mironska K
  90. Mogensen TH
  91. Morio T
  92. Ng LFP
  93. Notarangelo LD
  94. Novelli A
  95. Novelli G
  96. Ofarrelly C
  97. Okada S
  98. Okamoto K
  99. Ozcelik T
  100. Ozcelik F
  101. Panhammarstrom Q
  102. De Diego RP
  103. Pereztur J
  104. Perlin DS
  105. Peter J
  106. Planas AM
  107. Prando C
  108. Pujol A
  109. Puel A
  110. Quintanamurci L
  111. Ramaswamy S
  112. Renia L
  113. Resnick I
  114. Rodriguezgallego C
  115. Sanchoshimizu V
  116. Sediva A
  117. Seppanen MRJ
  118. Shahrooei M
  119. Shcherbina A
  120. Slaby O
  121. Snow AL
  122. Solerpalacin P
  123. Soumelis V
  124. Spaan AN
  125. Su HC
  126. Tancevski I
  127. Tangye SG
  128. Tayoun AA
  129. Temel SG
  130. Thorball C
  131. Tiberghien P
  132. Trouilletassant S
  133. Turvey SE
  134. Furkan Uddin KM
  135. Uddin MJ
  136. Van De Beek D
  137. Vianna FSL
  138. Vinh DC
  139. Von Bernuth H
  140. Wauters J
  141. Zatz M
  142. Zhang Q
  143. Zhang SY
  144. Benfield T
  145. Bodilsen J
  146. Hansen KS
  147. Helleberg M
  148. Storgaard M
  149. Pereira A
  150. De Oliveira Fam BS
  151. Sgarioni E
  152. Rodrigues GM
  153. Giudicelli GC
  154. Nunes K
  155. Pereira LV
  156. Rodrigues MR
  157. Feira MF
  158. Castro E Silva MA
  159. Wissmann MS
  160. Prado MJ
  161. Cadore NA
  162. Lemes RB
  163. Sbruzzi RC
  164. Artigalas O
  165. Hunemeier T
  166. Bureau S
  167. Vacher Y
  168. Gysemberghhoual A
  169. Demerville L
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  171. Abad S
  172. Abassi R
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  174. Abdelmalek A
  175. Abdoul H
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  177. Abeud F
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  189. Kaci MA
  190. Oufella HA
  191. Ajeenthiravasan G
  192. Alauzy V
  193. Albylaurent F
  194. Allard L
  195. Alyanakian MA
  196. Borrero BA
  197. Amam S
  198. Amrouche L
  199. Andronikof M
  200. Anglicheau D
  201. Anguel N
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  212. Audureau E
  213. Auger CN
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  219. Azzouguen B
  220. Elrufaai MB
  221. Badsi A
  222. Bakouboula P
  223. Balcerowiak C
  224. Balde F
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  226. Bangamingo EF
  227. Baptiste A
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  233. Baudel JL
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  239. Belilita R
  240. Bellassen P
  241. Belmokhtar R
  242. Beltran I
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  256. Bertier A
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  259. Beurton A
  260. Bianco C
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  262. Bidar F
  263. Blanche P
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  266. Blin E
  267. Blochqueyrat C
  268. Boissier MC
  269. Bollens D
  270. Bolzoni M
  271. Bompard RP
  272. Bonnet N
  273. Bonnouvrier J
  274. Botha S
  275. Boucenna W
  276. Bouchama F
  277. Bouchaud O
  278. Bouchghoul H
  279. Boudjebla T
  280. Boudjema N
  281. Bouffard C
  282. Bougle A
  283. Bouguerra M
  284. Bouras L
  285. Bourcier A
  286. Durand AB
  287. Bourrier A
  288. Bouscarat F
  289. Bouvry D
  290. Bouziri N
  291. Bouzrara O
  292. Bribier S
  293. Brugier D
  294. Brunel M
  295. Bui E
  296. Buisson A
  297. Bukreyeva I
  298. Bureau C
  299. Cadranel J
  300. Cailhol J
  301. Calin R
  302. Vega CC
  303. Canavaggio P
  304. Cancella M
  305. Cantin D
  306. Cao A
  307. Carbillon L
  308. Carlier N
  309. Cassard C
  310. Castor G
  311. Cauchy M
  312. Cha O
  313. Chaigne B
  314. Challal S
  315. Champion K
  316. Chariot P
  317. Chas J
  318. Chauveau S
  319. Chauvin A
  320. Chauvin C
  321. Chavarot N
  322. Chebbout K
  323. Cherai M
  324. Cherubini I
  325. Chevalier A
  326. Chiarabini T
  327. Chinet T
  328. Chocron R
  329. Choinier P
  330. Chommeloux J
  331. Choquet C
  332. Choupeaux L
  333. Chousterman B
  334. Ciocan D
  335. Clarke A
  336. Clavere G
  337. Clavier F
  338. Clement K
  339. Clerc S
  340. Cohen Y
  341. Cohen F
  342. Cohen A
  343. Coilly A
  344. Colboc H
  345. Colin P
  346. Collet M
  347. Comarmond C
  348. Combacon E
  349. Combes A
  350. Comparon C
  351. Constantin JM
  352. Cordel H
  353. Cordier AG
  354. Costantini A
  355. Chalumeau NC
  356. Couffignal C
  357. Coupeau D
  358. Creange A
  359. Lamarre YC
  360. Da Silveira C
  361. El Kayani SDG
  362. De Castro N
  363. De Rycke Y
  364. Del Pozo L
  365. Delannoy Q
  366. Delay M
  367. Deleris R
  368. Delforge J
  369. Delphine L
  370. Demare N
  371. Demeret S
  372. Demoule A
  373. Deniau A
  374. Depret F
  375. Derolez S
  376. Derradji O
  377. Derridj N
  378. Descamps V
  379. Deschamps L
  380. Desconclois C
  381. Desnos C
  382. Desongins K
  383. Dhote R
  384. Diallo B
  385. Didier M
  386. Diemer M
  387. Diez S
  388. Djadiprat J
  389. Monnory FZD
  390. Djebara S
  391. Djebra N
  392. Djietcheu M
  393. Djillali H
  394. Djouadi N
  395. Donneger S
  396. Dos Santos C
  397. Dournon N
  398. Dres M
  399. Droctove L
  400. Drogrey M
  401. Dropy M
  402. Drouet E
  403. Dubosq V
  404. Dubreucq E
  405. Dubus E
  406. Duchemann B
  407. Duchenoy T
  408. Dudoignon E
  409. Dufau R
  410. Dumas F
  411. Duran C
  412. Duron E
  413. Durrbach A
  414. Duvivier C
  415. Ebstein N
  416. El Khalifa J
  417. Elabbadi A
  418. Elie C
  419. Ernotte G
  420. Esling A
  421. Etienne M
  422. Eyer X
  423. Fartoukh MS
  424. Fayali T
  425. Fermaut M
  426. Fiorentino A
  427. Fliss S
  428. Fournier MC
  429. Fournier B
  430. Francois H
  431. Freynet O
  432. Frigout Y
  433. Fromont I
  434. Fuentes A
  435. Furet T
  436. Galand J
  437. Garnier M
  438. Gaubert A
  439. Gaudry S
  440. Gaugain S
  441. Gauthier D
  442. Gautier M
  443. Georginlavialle S
  444. Geromin D
  445. Ghalayini M
  446. Ghaleh B
  447. Ghezal M
  448. Gibelin A
  449. Gimeno L
  450. Girard B
  451. Leprieur BG
  452. Gomes D
  453. Gomespires E
  454. Gorochov G
  455. Gouge A
  456. Gouja A
  457. Goulet H
  458. Goupil S
  459. De Bouille JG
  460. Gras J
  461. Greffe S
  462. Grimaldi L
  463. Guedeney P
  464. Guidet B
  465. Guillo M
  466. Gulczynski M
  467. Hadjam T
  468. Haguenauer D
  469. Hammal S
  470. Hammoudi N
  471. Hanon O
  472. Harrois A
  473. Hausfater P
  474. Hautem C
  475. Hekimian G
  476. Heming N
  477. Hermine O
  478. Ho S
  479. Houllier M
  480. Huot B
  481. Huscenot T
  482. Saied WI
  483. Ikherbane G
  484. Imarazene M
  485. Ingiliz P
  486. Iratni L
  487. Jaureguiberry S
  488. Jeanmarc JF
  489. Jeyarajasingham D
  490. Jouany P
  491. Jouis V
  492. Jourdaine C
  493. Kafif O
  494. Kallala R
  495. Katsahian S
  496. Kelesyan L
  497. Keo V
  498. Ketz F
  499. Khamis W
  500. Khelili E
  501. Khellaf M
  502. Youkou CGK
  503. Kounis I
  504. Kpalma G
  505. Krause J
  506. Labbe V
  507. Lacombe K
  508. Lacorte JM
  509. Lafont AG
  510. Lafont E
  511. Lagha L
  512. Lamhaut L
  513. Lancelot A
  514. Landman C
  515. Lanternier F
  516. Larcheveque C
  517. Combe CL
  518. Lassel L
  519. Laverdant B
  520. Lavergne C
  521. Lavillegrand JR
  522. Lazureanu P
  523. Le Guennec L
  524. Leberre L
  525. Leblanc C
  526. Leboyer M
  527. Lecomte F
  528. Lecorre M
  529. Leenhardt R
  530. Lefebvre M
  531. Lefebvre B
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  533. Leger A
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  536. Lehuunghia S
  537. Lemarec J
  538. Leporrierext J
  539. Lesein M
  540. Lesur H
  541. Levy V
  542. Levy A
  543. Lopes E
  544. Lopes A
  545. Lopez V
  546. Lopinto J
  547. Lortholary O
  548. Louadah B
  549. Loze B
  550. Lucas ML
  551. Lucasamichi A
  552. Luong LB
  553. Magazimamaext A
  554. Maingret D
  555. Mameri L
  556. Manivet P
  557. Mansouri C
  558. Marcault E
  559. Marey J
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  561. Marois C
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  563. Martineau L
  564. Martinezlopez C
  565. Martyniuck P
  566. De Farcy PM
  567. Marzouk N
  568. Masmoudi R
  569. Mebazaa A
  570. Mechai F
  571. Mecozzi F
  572. Mediouni C
  573. Megarbane B
  574. Meghadecha M
  575. Mejean E
  576. Mekinian A
  577. Abdelhadi NM
  578. Mekni R
  579. Meliti TS
  580. Lima BM
  581. Meng P
  582. Merbah S
  583. Messani F
  584. Messaoudi Y
  585. Mewasing BI
  586. Meziane L
  587. Michelotburger C
  588. Mignot F
  589. Minka FH
  590. Miyara M
  591. Moine P
  592. Molina JM
  593. Montegniesboulet A
  594. Monti A
  595. Montlahuc C
  596. Montout AL
  597. Moores A
  598. Morbieu C
  599. Mortelette H
  600. Mouly S
  601. Muzaffar R
  602. Nacerddine CI
  603. Nadal M
  604. Nadif H
  605. Nassarmadji K
  606. Natella P
  607. Ndingamondze S
  608. Neraal S
  609. Nguyen C
  610. Nguyen B
  611. Larmurier IN
  612. Nlomenyengue L
  613. Noel N
  614. Nunes H
  615. Omar E
  616. Ouazene Z
  617. Ouedraogo E
  618. Ouelaa W
  619. Oukhedouma A
  620. Amara YO
  621. Oya H
  622. Oziel J
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  624. Paillaud E
  625. Paiva S
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  627. Parize P
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  634. Pernet J
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  637. Peyrony O
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  639. Pietri O
  640. De Chambrun MP
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  642. Pintado C
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  656. Provoost MJ
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  659. Rami A
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  662. Raphalen JH
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  664. Raux M
  665. Rebai A
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  667. Regent A
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  862. Perpoint T
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  890. Dechanet A
  891. Descamps D
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  896. Houhou N
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  899. Lucet JC
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  902. Quintin C
  903. Thy M
  904. Van Der Werf S
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Source: Proceedings of the National Academy of Sciences of the United States of America Published: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. Copyright © 2026 the Author(s).
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