@article{68e83dba5e424822938152603076ab19,
title = "Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus",
abstract = "Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. CypD−/− mice are significantly more susceptible to IAV infection despite comparable antiviral immunity. This susceptibility results from damage to the lung epithelial barrier caused by a reduction in interleukin-22 (IL-22)-producing natural killer (NK) cells. Transcriptomic and functional data reveal that CypD−/− NK cells are immature and have altered cellular metabolism and impaired IL-22 production, correlating with dysregulated bone marrow lymphopoiesis. Administration of recombinant IL-22 or transfer of wild-type (WT) NK cells abrogates pulmonary damage and protects CypD−/− mice after IAV infection. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.",
keywords = "CP: Immunology, CP: Microbiology, IL-22, NK cells, cyclophilin D, disease tolerance, influenza, lymphopoiesis",
author = "Jeffrey Downey and Randolph, {Haley E.} and Erwan Pernet and Tran, {Kim A.} and Khader, {Shabaana A.} and King, {Irah L.} and Barreiro, {Luis B.} and Maziar Divangahi",
note = "Funding Information: The authors would like to thank members of the Small Animal Imaging Labs, particularly Dr. Barry Bedell and Mathieu Simard, and the Histopathology Core of the RI-MUHC, as well members of the Institut de Recherches Cliniques de Montr{\'e}al for the generation and sequencing of RNA-seq libraries. Models were created by BioRender.com . This work was supported by the Canadian Institute of Health Research Project Grant ( 168885 ) to M.D. M.D. holds a Fonds de Recherche du Qu{\'e}bec–Sant{\'e} Award and the Strauss Chair in Respiratory Diseases . J.D. was supported by the Molson Foundation Award and H.E.R. by a National Science Foundation Graduate Research Fellowship ( DGE-1746045 ). Funding Information: The authors would like to thank members of the Small Animal Imaging Labs, particularly Dr. Barry Bedell and Mathieu Simard, and the Histopathology Core of the RI-MUHC, as well members of the Institut de Recherches Cliniques de Montr{\'e}al for the generation and sequencing of RNA-seq libraries. Models were created by BioRender.com. This work was supported by the Canadian Institute of Health Research Project Grant (168885) to M.D. M.D. holds a Fonds de Recherche du Qu{\'e}bec–Sant{\'e} Award and the Strauss Chair in Respiratory Diseases. J.D. was supported by the Molson Foundation Award and H.E.R. by a National Science Foundation Graduate Research Fellowship (DGE-1746045). M.D. conceived and supervised the project. J.D. and M.D. designed the experiments; J.D. E.P. and K.A.T. performed experiments. Data were analyzed and interpreted by J.D. and M.D. except for RNA-seq data analyses, which were performed by H.E.R. under the supervision of L.B.B. I.L.K. and S.A.K provided technical input, expertise, and manuscript review. J.D. H.E.R. L.B.B. and M.D. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jun,
day = "21",
doi = "10.1016/j.celrep.2022.110974",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
number = "12",
}