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| Status |
Public on Jun 21, 2022 |
| Title |
Cyclophilin D promotes disease tolerance to influenza A virus infection by licensing NK cell development and function |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
An effective immune response to influenza A virus (IAV) requires two arms: host resistance, which restricts viral replication, and disease tolerance that limits tissue damage caused by the immune response to IAV. Interestingly, fatal influenza infections are more often associated with dysregulated inflammation, rather than an inability to control viral replication, highlighting the importance of mechanisms involved in disease tolerance to IAV. Here, we show that cyclophilin D (CypD), a mitochondrial protein known to regulate cell death and cytokine production, protects against IAV infection through disease tolerance. Mice deficient in CypD (CypD-/-) exhibit enhanced susceptibility to IAV infection, despite comparable myeloid immune responses and intact antiviral immunity. Instead, CypD-/- susceptibility was due to pulmonary tissue damage, caused by a lack of the cytokine IL-22 that protects the lung epithelium. We found the necessary source of IL-22 following IAV infection to be conventional natural killer (NK) cells that failed to reach the airways of infected CypD-deficient mice, as a result of dysregulated lymphopoiesis in the bone marrow. Importantly, following infection, a single administration of recombinant IL-22 in the airways abrogated pulmonary damage and rescued CypD-/- mice. Thus, the CypD/IL-22/NK cell axis is critical in immunity to IAV by promoting disease tolerance, limiting lung tissue damage and maintaining pulmonary function.
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| Overall design |
RNA expression profiles of control (uninfected) and influenza-infected purified splenic natural killer (NK) cells from wild type (WT) and CypD knockout mice
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| Contributor(s) |
Downey J, Randolph HE, Pernet E, Tran KA, Khader SA, Barriero LB, Divangahi M |
| Citation missing |
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| Submission date |
Dec 15, 2020 |
| Last update date |
Jun 21, 2022 |
| Contact name |
Luis B Barreiro |
| E-mail(s) |
barreirolabchicago@gmail.com
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| Organization name |
University of Chicago
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| Lab |
Barreiro Lab
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| Street address |
900 E 57th Street
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| City |
Chicago |
| ZIP/Postal code |
60637 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA685547 |
| SRA |
SRP298064 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE163290_Mus_musculus.mm10.81.kallisto.gene_level.lengthScaledTPM_counts.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
| GSE163290_Mus_musculus.mm10.81.kallisto.gene_level.raw_counts.txt.gz |
4.4 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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