Coxsackievirus group B3 regulates ASS1-mediated metabolic reprogramming and promotes macrophage inflammatory polarization in viral myocarditis.

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  • Additional Information
    • Source:
      Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Society For Microbiology
      Original Publication: Baltimore, American Society for Microbiology.
    • Subject Terms:
      Myocarditis*/virology ; Myocarditis*/metabolism ; Myocarditis*/immunology ; Myocarditis*/pathology ; Enterovirus B, Human*/physiology ; Macrophages*/virology ; Macrophages*/metabolism ; Macrophages*/immunology ; Coxsackievirus Infections*/virology ; Coxsackievirus Infections*/immunology ; Coxsackievirus Infections*/metabolism ; Argininosuccinate Synthase*/metabolism; Animals ; Mice ; Humans ; Male ; Inflammation/metabolism ; Myocardium/metabolism ; Myocardium/pathology ; Myocardium/immunology ; Capsid Proteins/metabolism ; Capsid Proteins/immunology ; Metabolic Reprogramming
    • Abstract:
      Coxsackievirus group B3 (CVB3) belongs to the genus Enteroviruses of the family Picornaviridae and is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, and then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for treating this disease.
      Importance: Viral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3, and discovered the therapeutic potential of citrulline for VMC.
      Competing Interests: The authors declare no conflict of interest.
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    • Grant Information:
      82203032,32260193 MOST | National Natural Science Foundation of China (NSFC); 32060040 MOST | National Natural Science Foundation of China (NSFC); 20212BCJ23036 Training Plan for Academic and Technical Leaders of Major Disciplines in Jiangxi Province-Youth Talent Project; jxsq2023301110, jxsq2023201019 Project for high and talent of Science and Technology Innovation in Jiangxi Double-Thousand Program of Jiangxi Province; 202310403042, 202410403095, 202410403097 National Innovation and Entrepreneurship Training Program for college students
    • Contributed Indexing:
      Keywords: argininosuccinate synthase 1; coxsackievirus group B3; macrophages; viral myocarditis
    • Accession Number:
      EC 6.3.4.5 (Argininosuccinate Synthase)
      0 (Capsid Proteins)
    • Publication Date:
      Date Created: 20240828 Date Completed: 20240917 Latest Revision: 20240919
    • Publication Date:
      20240919
    • Accession Number:
      PMC11406948
    • Accession Number:
      10.1128/jvi.00805-24
    • Accession Number:
      39194244