Evaluating the role of IRG1 and itaconate on Marek's Disease virus infection
Date
2022
Authors
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Publisher
University of Delaware
Abstract
Marek’s Disease (MD) is an oncogenic pathology of chickens characterized by paralysis, immune suppression, and the induction of T-cell lymphomas. The causative agent of MD is the Alphaherpesvirus Marek’s Disease Virus (MDV), which is spread through the inhalation of infectious dander particles. In response to viral infection, it is postulated that immune responsive gene 1 (IRG1) is upregulated as an immunomodulator. IRG1, is induced in macrophages during inflammation and generates itaconic acid (ITA). ITA has multiple functions mediated by its conjugation to cellular, viral, and bacterial proteins. For instance, ITA inhibits succinyl dehydrogenase, causing a shift in metabolism from the tricarboxylic acid cycle to glycolysis during immune response. ITA is conjugated onto several viral proteins, inhibiting their function. Of note, ITA also regulates the levels of nuclear erythroid related factor 2 (NRF2) through the dissociation of Kelch like ECH Associated Protein 1 (KEAP1). NRF2 is a transcription factor that regulates anti-inflammatory and anti-oxidative genes. In recent studies, NRF2 has been found to produce an antiviral effect. NRF2 is also thought to be involved in carcinogenic processes due to its anti-oxidative effects. ☐ We have examined IRG1 expression during MDV pathogenic (rMd5) and vaccine (rMd5∆Meq) virus replication, in vivo. We found that IRG1 was induced at 4 dpi by rMd5 and then downregulated, while IRG1 was significantly induced at 7, 14 and 21 dpi during rMd5∆Meq replication. Using a cell-permeable derivative of ITA (4-octyl itaconate, 4OI), we found that this chemical inhibits MDV replication in chicken embryo fibroblasts (CEF) and spleen cells during the lytic phase (7 dpi) of viral replication. Together, our data provide some mechanistic understanding of how IRG1 may be important to MDV resistance and pathogenesis.
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Keywords
Immunometabolism, IRG1, Itaconate, Marek's Disease, Metabolic reprogramming, NRF2