Unraveling SOCS-2 as a key mediator of beta-coronavirus infection pathogenesis and co-infection in chronic Chagas Disease.

Abstract

COVID-19 exacerbates pre-existing comorbidities, including Chagas Disease (CD). Suppressor of Cytokine Signaling (SOCS)-2 regulates inflammation, but its role in chronic CD and Coronavirus 2 (SARS-CoV-2) virus infection is unclear. In a murine model of chronic CD and murine hepatitis virus (MHV-3) infection/co-infection, we found that SOCS-2 expression increased in wild-type target organs in all infection models. SOCS-2 knockout (SO2 KO) mice showed significant cardiac impairment, especially during co-infection, which was associated with heightened parasitism. Additionally, in the absence of SOCS-2 co-infection affect lung function is characterized by a high viral load in the lungs and is associated with an unbalanced immune response. In contrast, WT mice displayed a robust TNF response in macrophages and dendritic cells, leading to more effective viral clearance and preserved lung function. Furthermore, SOCS-2 deficiency resulted in severe intestinal damage, including greater mucosal loss and dysbiosis. In co-infection, increased parasitism in the intestine was observed in SO2 KO mice, accompanied by a higher proportion of IL-10innate and adaptive cells, and dendritic cells showed an absolute absence of TNF, along with a reduced proportion of T CD4IFN-γand T CD4IL-17cells and lower production of these cytokines by T CD8cells in comparison to WT co-infected mice. These findings emphasize the pivotal role of SOCS-2 in modulating immune responses and mitigating disease progression in chronic CD and CD-MHV-3 co-infections.