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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Article number110974
JournalCell Reports
Volume39
Issue number12
DOIs
StatePublished - Jun 21 2022

Keywords

  • CP: Immunology
  • CP: Microbiology
  • IL-22
  • NK cells
  • cyclophilin D
  • disease tolerance
  • influenza
  • lymphopoiesis

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