Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus

Jeffrey Downey; Haley E Randolph; Erwan Pernet; Kim A Tran; Shabaana A Khader; Irah L King; Luis B Barreiro; Maziar Divangahi

doi:10.1016/j.celrep.2022.110974

Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus

Cell Rep. 2022 Jun 21;39(12):110974. doi: 10.1016/j.celrep.2022.110974.

Authors

Jeffrey Downey¹, Haley E Randolph², Erwan Pernet¹, Kim A Tran¹, Shabaana A Khader³, Irah L King¹, Luis B Barreiro⁴, Maziar Divangahi⁵

Affiliations

¹ Department of Medicine, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada; Department of Pathology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada; Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
² Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA.
³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁵ Department of Medicine, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada; Department of Pathology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada; Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada. Electronic address: maziar.divangahi@mcgill.ca.

PMID: 35732121
DOI: 10.1016/j.celrep.2022.110974

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Influenza A virus*
Influenza, Human*
Interleukin-22
Interleukins
Killer Cells, Natural
Mice
Mice, Inbred C57BL
Mitochondria* / metabolism
Orthomyxoviridae Infections*
Peptidyl-Prolyl Isomerase F

Substances

Peptidyl-Prolyl Isomerase F
Interleukins

Grants and funding

168885/CIHR/Canada