Targeting innate immune pathways, and inflammatory cell death in cytokine-mediated diseases

ABSTRACT The innate immune system is the critical first line of defense against pathogenic infections. In the context of viral infections, activation of the innate immune response is key to controlling viral replication and eliminating the infection. However, overactivation of this response can lead to systemic hyperinflammation and significant morbidity and mortality. Recently, a novel coronavirus, SARS-CoV-2, has emerged, leading to the disease COVID-19 and a global pandemic. Targeted therapeutic strategies are critically lacking, and there is limited understanding of the role of innate immune responses in this disease. Clinical data show that patients with COVID-19 experience a cytokine storm and significant tissue damage, both of which contribute to disease severity and mortality. Recent work from our group showed that increased TNF-α and IFN-γ levels following SARS-CoV-2 infection lead to inflammatory cell death, which is detrimental to the host. We found that neutralizing TNF-α and IFN-γ reduced SARS-CoV-2-induced mortality in mice. But little is known about the mechanistic basis behind the uncontrolled cytokine release. While several potential therapies to block different inflammatory cytokines are being explored, balancing proinflammatory responses to clear the virus with preventing systemic inflammation remains challenging. Improved understanding of the mechanisms by which the innate immune system recognizes and responds to coronavirus infections will be key to informing and developing therapeutic strategies. Furthermore, the roles of specific innate immune sensors, inflammasome activation, and inflammatory cell death in COVID-19 disease development remain unknown. We have previously elucidated the molecular details of innate immune signaling pathways that regulate inflammation and pathogenic clearance, identifying upstream sensors and important molecules in these pathways. In this grant application, we seek to unravel the fundamental mechanisms of novel innate immune sensors and inflammasome regulators discovered in our lab previously and understand their crosstalk with cell death regulators in coronavirus infection. Basic science supporting this area of research is critical to understanding the fundamentals of the innate immune response. The work completed under this proposal will characterize the major innate immune sensors that are directly sensing SARS-CoV-2 to initiate interferon and inflammatory cytokine expression and identify the molecular mechanisms that regulate inflammatory cell death in response to SARS-CoV-2. These discoveries are expected to identify novel signaling pathways that could be targeted by therapeutic interventions. The findings will be applicable to not only COVID-19, but also other infectious diseases and conditions associated with a hyperactive innate immune response, cytokine release, and severe inflammation; this work will be fundamental to inform clinical directions to prevent morbidity and mortality.