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Cyclophilin D promotes disease tolerance to influenza A virus infection by licensing NK cell development and function

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE163290 | GEO | 2022/06/21

REPOSITORIES: GEO

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Arhgdia regulates disease tolerance in IAV-infected epithelial cells

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Project description:The immune protection against invading pathogens is governed by pathogen elimination (‘resistance’) and by limitation of tissue damage that results from host-pathogen interactions (‘tolerance’). However, distinct molecular states of resistance and tolerance remain obscure. Here, we collected longitudinal lung transcriptomes and clinical phenotypes of disease severity during influenza A virus (IAV) infection across 39 genetically-distinct mouse strains (32 strains of time series data and additional 7 strains with selected time points). Using transcriptional diversity in this data, we uncovered two key programs that together describe the cellular states for resistance and tolerance. The identified programs offer an unprecedented comprehensive view on shared and distinct roles of resistance and tolerance for the regulation of immune defense – for instance, we identified an antagonistic regulation of resistance and tolerance on protein production. Importantly, the framework reveals that both inflammatory states and the healthy steady state are remarkably diverse in resistance and tolerance levels, with implications on disease severity: a baseline state (before infection) of high tolerance and low resistance results in increased severity of IAV infection. Overall, our work provides a framework for the study of resistance and tolerance that could aid in clinical diagnosis and disease management.

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Project description:The aim of this study was to acquire a better understanding of porcine reproductive and respiratory syndrome (PRRS) disease through a deeper knowledge of gene expression changes that occur in pulmonary lymph nodes by comparing PRRS virus (PRRSV), porcine circovirus type 2 (PCV-2), and swine influenza virus (IAV-S) infections. The PRRSV, IAV-S and PCV-2 viral infections followed a clinical course in these domestic pigs typical of experimental infection of young pigs with these viruses. PRRSV isolate SDSU-73 was pathogenic in this study inducing fever, anorexia, listlessness, and dyspnea.

2018-03-03 | GSE111378 | GEO

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