Show simple item record

dc.contributor.authorSohail, Aaqib
dc.contributor.authorIqbal, Azeem A
dc.contributor.authorSahini, Nishika
dc.contributor.authorChen, Fangfang
dc.contributor.authorTantawy, Mohamed
dc.contributor.authorWaqas, Fakhar
dc.contributor.authorWinterhoff, Moritz
dc.contributor.authorEbensen, Thomas
dc.contributor.authorSchultz, Kristin
dc.contributor.authorGeffers, Robert
dc.contributor.authorSchughart, Klaus
dc.contributor.authorPreusse, Matthias
dc.contributor.authorShehata, Mahmoud
dc.contributor.authorBähre, Heike
dc.contributor.authorPils, Marina C
dc.contributor.authorGuzman, Carlos A
dc.contributor.authorMostafa, Ahmed
dc.contributor.authorPleschka, Stephan
dc.contributor.authorFalk, Christine
dc.contributor.authorMichelucci, Alessandro
dc.contributor.authorPessler, Frank
dc.date.accessioned2022-02-15T09:24:24Z
dc.date.available2022-02-15T09:24:24Z
dc.date.issued2022-01-13
dc.identifier.citationPLoS Pathog. 2022 Jan 13;18(1):e1010219. doi: 10.1371/journal.ppat.1010219. Epub ahead of print.en_US
dc.identifier.pmid35025971
dc.identifier.doi10.1371/journal.ppat.1010219
dc.identifier.urihttp://hdl.handle.net/10033/623164
dc.description.abstractExcessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. Itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.en_US
dc.language.isoenen_US
dc.publisherPLOSen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleItaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.en_US
dc.typeArticleen_US
dc.identifier.eissn1553-7374
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalPLoS pathogensen_US
dc.source.volume18
dc.source.issue1
dc.source.beginpagee1010219
dc.source.endpage
refterms.dateFOA2022-02-15T09:24:25Z
dc.source.journaltitlePLoS pathogens
dc.source.countryUnited States


Files in this item

Thumbnail
Name:
Sohail et al.pdf
Size:
18.87Mb
Format:
PDF
Description:
Open Access publication

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International