Innate immunological pathways in COVID-19 pathogenesis

Abstract

Coronavirus disease 2019 (COVID-19) is a disease characterized by a profound dysregulation of the innate immune system. This knowledge has emerged from the large body of single-cell omics studies of patients with COVID-19, which have provided one of the most detailed cellular atlases of a human disease ever. However, we are only beginning to understand the innate immunological pathways that govern host defense and immunopathology in COVID-19. In this review, we discuss the emerging understanding of how SARS-CoV-2 and host-derived molecules activate specific pattern recognition receptors to elicit protective interferon responses and pathological cytokine responses, with particular focus on acute infection of the lung and lung pathophysiology in critical COVID-19. In addition, we discuss how these pathways are modulated by virus-host interactions and host stress-sensing pathways. In-depth understanding of the disease mechanisms will likely uncover specific molecular targets for the treatment of COVID-19 and other emerging viral infections. In addition, it will reveal the fine balance between beneficial protective versus pathological disease causing immune responses.

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

“…Triggering type I IFN production and release is a crucial outcome of PRR signaling, as type I IFN unleash autocrine and paracrine antiviral responses [ 30 ]. Research is currently defining the precise role of PRRs in sensing SARS-CoV-2, building on the knowledge of coronavirus infection [ 31 ]. Therefore, this contributes to the understanding of ubiquitin in antiviral signaling and defense in COVID-19 [ 32 ].…”

“…The severity of COVID-19 can widely vary between patients. Innate immune sensing and the subsequent activation of the adaptive immune response seem to play a critical role in this [ 31 ].…”

Pharmacological inhibition of TBK1/IKKε blunts COVID-19 immunopathology

“…Although the protective effect of STING inhibition was not time-dependent, and was replicated with prophylactic administration 35 , we note that early TBK1 inhibition would be expected to fuel viral replication, since early type-I anti-viral responses are driven by RNA sensors, including RIG-I and MDA5 30 . However, we found that late administration of IDX did not impact the viral load measured in the lungs of SARS-CoV-2-infected mice, while concurrently dampening critical inflammatory factors associated with severe COVID-19 in patients (e.g., TNF, IL-6, and IFN-g) and decreasing airway neutrophil infiltration which correlates with disease severity [36][37][38][39][40] .…”

Persistent Immune and Clotting Dysfunction Detected in Saliva and Blood Plasma after COVID-19

“…It warrants that neutrophildriven innate immune response at oral mucosa initiates a dysbiotic cycle, tissue damage that ultimately leads to prolonged infection-inflammation sequelae. In severe COVID-19 cases, neutrophil degradation and NETosis in blood and lung have been functionally linked to severe inflammation and thrombosis 14,15,[47][48][49][50] . These molecular consequences of COVID-19 are now well studied.…”