Impacts of Ccr2+ Inflammatory Monocytes and Cxcr3-Bearing T Cells on Metabolic Reprogramming during Influenza a Virus Infection

Influenza A virus (IAV) is the most common human respiratory virus that causes seasonal epidemic and pandemic infections. Aside from young children and the elderly, the highest risk of complications occurs in individuals with metabolic syndromes, such as diabetes, obesity, and cardiopulmonary disease. Pathologically, severe viral pneumonia is characterized by inflammatory infiltrates, edema and hemorrhage and bronchitis and bronchiolitis. Immunologically, excessive and prolonged innate immune responses are accompanied by high virus loads. The reasons of cause epidemic and pandemic infection by IAV are commonly explained by two main issues. One is gene reassortment and gene mutation of IAV. The other is IAV-induced cytokine storm that is frequently observed in severe infection, with the induction of excessive proinflammatory cytokine production, including IL-6, IL-8, CCL2, CCL12, CXCL9 and CXCL10. Based on our previous study, recuirtment of CCR2+ inflammatory monocytes is amplified by an IFNAR1-triggered feedback loop of CCR2 ligands, including CCL2, CCL7 and CCL12. Recently, we further investigate that CXCR3 ligands, CXCL9 and CXCL10, produced from CCR2+ inflammatory monocytes are responsible for the recruitment of CXCR3+ effector T cells into inflamed lung. So, three major goals are proposed in this grant. (1) To study the metabolic reprogramming in CCR2+ inflammatory monocytes and CXCR3+ T cells. Until now, the metabolic processing of amino acids during acute respiratory infection and the consequences of metabolic alteration in severe inflammation are unclear. To comprehensively examine the metabolic alteration during acute respiratory infection, 19 amino acids are screened. Of interest, the alteration of Trp and Arg is highly associated with heavy leukocyte infiltration, but less associated with virus loads. Several reports show the relationship between Trp and Arg, and immune response. So, it will be worth to further confirm our results. (2) To explore the regulatory mechanism of Trp and Arg in IAV infected mice. Several lines of immune related gene deficiencies mice are used to address which gene(s) may be involved in this Trp and Arg alteration such as Ifnar1-/-, Ifn-/- and Stat1-/- mice. Preliminarily, we find that both type I and type II IFNs are involved in regulation of Trp and Arg metabolic enzymes, including indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase (iNOS) and Arginase 1. These three enzymes have been reported correlated with immune regulation in cancers. So, the expression amount and regulatory mechanism of three enzymes in IAV infection may help to more understand the roles of Trp and Arg in IAV infection. (3) To evaluate the potency of IDO, iNOS and Arginase 1 inhibitors in IAV infection. Up to date, it seems that the vaccination is the only way to prevent IAV infection and Tamiflu is the most potent ativiral drug against IAV. However, the vaccination does not always work and Tamiflu-resistant strain is found in clinic. So, we would like to develop new strategies to prevent or cure IAV infection. Based on our preliminary data, the inhibitors of IDO, iNOS and Arginase 1 may protect IAV infection. This information may provide valuable information for develop new avenue for IAV prevention or therapy.

Project ID:PC10607-0366
External Project ID:MOST106-2320-B182-022