Speaker
Description
Aconitate decarboxylase 1 (ACOD1) catalyzes the conversion of cis-aconitate to itaconic acid, and its activity is highly regulated in sterile inflammation and host responses to some bacterial pathogens. Very little is known about its role in anti-viral defenses. We have therefore used targeted deletion of ACOD1 in mice and THP-1 cells, as well as exogenous addition of itaconic acid and dimethyl-itaconic acid, to study the role of the ACOD1-itaconic acid axis in host defenses against influenza A virus (IAV). ACOD1 mRNA was highly expressed in wild-type mouse lungs 48 h post infection with IAV (H1N1)PR/8/34. Weight loss, mortality, and histopathologic changes in lung were higher in ACOD1-/- than in +/+ mice. Infected ACOD1-/- THP-1 cells exhibited higher IAV hemagglutinin expression and higher inflammation, particularly in type I IFN-regulated pathways, than wild-type cells. This effect was reversed upon exogenous addition of itaconic acid or dimethyl-itaconic acid, and it correlated with suppression of pathogenetically important pathways, but increased release of the anti-inflammatory polypeptide IL-1ra. In infected A549 cells, exogenous addition of both compounds markedly reduced IFN responses and TLR signaling pathways without affecting viral replication. Computational network analysis identified the NFkB inhibitors IkBa and IkBz as master regulators of the immunomodulatory effects. These results provide first evidence that the ACOD1-itaconic acid axis constitutes a crucial link in protective host responses to IAV infection, likely due to limiting inflammation and associated end-organ damage. Furthermore, they suggest that itaconic and dimethyl-itaconic acid merit further evaluation as adjunct, immunomodulatory treatments in influenza infection in humans.
| Choose secondary Session | Pathogenesis |
|---|---|
| Choose primary session | Innate Immunity |
