Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.
Excessive 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010219 |
| _version_ | 1811321659592802304 |
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| author | Aaqib Sohail Azeem A Iqbal Nishika Sahini Fangfang Chen Mohamed Tantawy Syed F H Waqas Moritz Winterhoff Thomas Ebensen Kristin Schultz Robert Geffers Klaus Schughart Matthias Preusse Mahmoud Shehata Heike Bähre Marina C Pils Carlos A Guzman Ahmed Mostafa Stephan Pleschka Christine Falk Alessandro Michelucci Frank Pessler |
| author_facet | Aaqib Sohail Azeem A Iqbal Nishika Sahini Fangfang Chen Mohamed Tantawy Syed F H Waqas Moritz Winterhoff Thomas Ebensen Kristin Schultz Robert Geffers Klaus Schughart Matthias Preusse Mahmoud Shehata Heike Bähre Marina C Pils Carlos A Guzman Ahmed Mostafa Stephan Pleschka Christine Falk Alessandro Michelucci Frank Pessler |
| author_sort | Aaqib Sohail |
| collection | DOAJ |
| description | Excessive 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. All three 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. |
| first_indexed | 2024-04-13T13:21:39Z |
| format | Article |
| id | doaj.art-566eee10fa3944c78bd62fa5ef5ffdb5 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-13T13:21:39Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-566eee10fa3944c78bd62fa5ef5ffdb52022-12-22T02:45:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-01-01181e101021910.1371/journal.ppat.1010219Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.Aaqib SohailAzeem A IqbalNishika SahiniFangfang ChenMohamed TantawySyed F H WaqasMoritz WinterhoffThomas EbensenKristin SchultzRobert GeffersKlaus SchughartMatthias PreusseMahmoud ShehataHeike BähreMarina C PilsCarlos A GuzmanAhmed MostafaStephan PleschkaChristine FalkAlessandro MichelucciFrank PesslerExcessive 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. All three 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.https://doi.org/10.1371/journal.ppat.1010219 |
| spellingShingle | Aaqib Sohail Azeem A Iqbal Nishika Sahini Fangfang Chen Mohamed Tantawy Syed F H Waqas Moritz Winterhoff Thomas Ebensen Kristin Schultz Robert Geffers Klaus Schughart Matthias Preusse Mahmoud Shehata Heike Bähre Marina C Pils Carlos A Guzman Ahmed Mostafa Stephan Pleschka Christine Falk Alessandro Michelucci Frank Pessler Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. PLoS Pathogens |
| title | Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. |
| title_full | Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. |
| title_fullStr | Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. |
| title_full_unstemmed | Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. |
| title_short | Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. |
| title_sort | itaconate and derivatives reduce interferon responses and inflammation in influenza a virus infection |
| url | https://doi.org/10.1371/journal.ppat.1010219 |
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