Between immunomodulation and immunotolerance: The role of IFNγ in SARS-CoV-2 disease

Abstract

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.

Neutralizing antibody and T cell responses against SARS-CoV-2 variants of concern following ChAdOx-1 or BNT162b2 boosting in the elderly previously immunized with CoronaVac vaccine

“…We speculated that the induction of IL-17 and FasL in T cells after vaccination might play an important role in immunity to SARS-CoV-2 infection, particularly for VOCs. IFN-γ is a pleiotropic cytokine that plays a role in protection against viral infection by regulating effector cells in both innate and adaptive immunity [ 45 – 47 ]. Several IFN-γ-orchestrated mechanisms contributing to the host antiviral response have been reported [ 45 ].…”

“…IFN-γ is a pleiotropic cytokine that plays a role in protection against viral infection by regulating effector cells in both innate and adaptive immunity [ 45 – 47 ]. Several IFN-γ-orchestrated mechanisms contributing to the host antiviral response have been reported [ 45 ]. Therefore, the effects of vaccination on the induction of IL-17A, IFN-γ, and FasL in CD4 and CD8 T cells were determined in our experiments.…”

The Immunology of SARS-CoV-2 Infection and Vaccines in Solid Organ Transplant Recipients

“…Treatment with the antiviral drug arbidol and IFNα-1b was reported to reduce the severity of illness in patients with moderate COVID-19 pneumonia [118]. A few small clinical trials in COVID-19 patients who received a subcutaneous injection of IFN-a2a or intranasal IFN-α2a or IFN-α2b reported faster recovery from the disease and faster virus clearance [119][120][121].…”

Distinct Cytokine Profiles in Severe COVID-19 and Non-Alcoholic Fatty Liver Disease

“…The synthesis of IFN-γ by Th1 CD4+ T cells induces the de novo synthesis of CXCL10 and perpetuates the inflammatory immune responses [ 29 ]. Meanwhile, IFN-γ is a Th1-type cytokine that exhibits antiviral, antiproliferative, and immunomodulatory activity [ 30 ]. Low IFN-γ concentrations are a poor prognostic factor in COVID-19 and are associated with an increased chance of developing pulmonary fibrosis [ 30 , 31 ].…”

“…Meanwhile, IFN-γ is a Th1-type cytokine that exhibits antiviral, antiproliferative, and immunomodulatory activity [ 30 ]. Low IFN-γ concentrations are a poor prognostic factor in COVID-19 and are associated with an increased chance of developing pulmonary fibrosis [ 30 , 31 ]. Contrarily, elevated levels of CXCL10 were reported to be associated with COVID-19 severity and mortality [ 32 ].…”