Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.

Autor: Sohail A; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany., Iqbal AA; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany., Sahini N; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany., Chen F; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany., Tantawy M; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany.; Hormones Department, Medical Research and Clinical Studies Institute, National Research Center, Dokki, Giza, Egypt.; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Center, Dokki, Giza, Egypt., Waqas SFH; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany., Winterhoff M; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany., Ebensen T; Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany., Schultz K; Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany., Geffers R; Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany., Schughart K; Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany.; University of Veterinary Medicine Hannover, Hannover, Germany.; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America., Preusse M; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany., Shehata M; Institute for Medical Virology, Justus-Liebig-University, Giessen, Germany.; Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, Egypt., Bähre H; Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany., Pils MC; Mouse Pathology Platform, Helmholtz Centre for Infection Research, Braunschweig, Germany., Guzman CA; Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany., Mostafa A; Institute for Medical Virology, Justus-Liebig-University, Giessen, Germany.; Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, Egypt., Pleschka S; Institute for Medical Virology, Justus-Liebig-University, Giessen, Germany.; German Center for Infection Research (DZIF) partner site Giessen, Germany., Falk C; Department of Transplantation Immunology, Hannover Medical School, Hannover, Germany., Michelucci A; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg.; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Pessler F; Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.; TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany.; Centre for Individualised Infection Medicine, Hannover, Germany.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2022 Jan 13; Vol. 18 (1), pp. e1010219. Date of Electronic Publication: 2022 Jan 13 (Print Publication: 2022).
DOI: 10.1371/journal.ppat.1010219
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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