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Influenza A virus-triggered succinylation in lung epithelial cells

ABSTRACT: Influenza A virus (IAV) is the etiological agent of a highly contagious acute respiratory disease, which causes a considerable socioeconomic burden despite annual vaccination campaigns. Therefore, it is essential to better understand IAV-host cells interaction to help design innovative antiviral therapies. In that regard, recent studies revealed the interplay between metabolic and immune signaling pathways. However, it remains unknown whether IAV alters lung tissues metabolism and what is its potential functional consequence. Using in vitro and in vivo models as well as human respiratory fluids and in-depth metabolomics analysis, we first found that IAV infection alters the glycolysis and mitochondrial oxidative respiration in lung tissues, leading to the accumulation of several immunometabolites in the bronchoalveolar airspaces. We next focused on one mitochondria-derived metabolite, i.e. succinate as its accumulation was found not only in the lungs of IAV-challenged mice but also in the tracheal fluids of IAV-infected patients. Remarkably, we found that succinate exhibits a potent antiviral activity both in vitro and in vivo as it inhibits H1N1 and H3N2 IAV strains and it strongly decreases IAV-triggered inflammatory response. The underlying inhibiting mechanism involves a disruption of IAV replication cycle. Indeed, succinate prevents specifically the nuclear export of the viral nucleoprotein NP, likely due to a specific succinylation at K87 site. Finally, we showed that mice receiving succinate through the intranasal route are more resistant to IAV pneumonia than mock-treated animals. Hence, our study identifies the metabolite succinate as a novel component of the host antiviral arsenal.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Bronchial Epithelial Cell

DISEASE(S): Influenza

SUBMITTER: Valentin SABATET

LAB HEAD: Damarys Loew

PROVIDER: PXD018419 | Pride | 2022-03-24

REPOSITORIES: Pride

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Project description:E2 exposure significantly decreased peak viral titer in hNECs from female donors. We used microarray analyses to identify global gene expression patterns between E2 and vehicle exposed hNECs from female donors Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17Î²-estradiol (E2) or select estrogen receptor modulators (SERMs), then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects where sex-dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor- 2 (ESR2) as neither genomic ESR1 nor non- genomic GPR30 were expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion, but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans. Primary human nasal epithelial cells from females were exposed to E2 for 24h prior to infection, then infected with an H3N2 strain of influenza a virus for 2 hours. At 24 and 48h post infection, hNECs were collected in Trizol for RNA extraction and hybridization on Affymetrix Human Gene ST 2.0 microarrays.

Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.

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Influenza A virus-triggered succinylation in lung epithelial cells

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