PAMPS and DAMPS mediate innate immune signalling
Infected pneumocytes and other permissible cells undergo cell damage and cell death releasing virally-associated molecules so-called ‘pathogen associated molecular patterns’ (PAMPS). In addition, intracellular components released due to damage so-called ‘damage or danger associated molecular patterns’ (DAMPS) include ATP, oxidized lipids, heat shock proteins and other components associated with regulated cell death programmes including apoptosis, autophagy, necroptosis, and pyroptosis [figure 3 and 4]. Thus, both DAMPS and PAMP contribute to innate immune actiavtion in COVID-19.
RNA viruses trigger several TLRs including TLR7/8 and TLR3, and elegant molecular in silco docking studies show that the spike protein of SARS‐CoV‐2 can bind to TLR1, TLR4, and TLR6 (73) (figure 3) whereasin vitro the SARS-CoV spike protein triggers NFκB activation and IL-8 production via TLR2 signalling in human peripheral blood mononuclear cells (74). In mice in which specific points in the TLR pathway were deleted i.e. TLR3−/−, TLR4−/−, and TRAM−/−, animals were more susceptible to SARS-CoV infection although the clinical severity of disease was dramatically reduced. This was in direct contrast to deficiency in TRIF, the TLR adaptor protein [figure 3] in which TRIF-/- mice developed severe disease, exacerbated influx of macrophages and neutrophils, and lung pathology indicative of COVID-19 pathology. Thus, a balanced response to infection via TLR3 pathway is essential to trigger a protective response to SARS-CoV (75). This study also supports the idea that in addition PAMPS, immune pathways triggered by DAMPS such as oxidised phospholipids, high mobility group box 1 (HMGB1), histones, heat shock proteins and adenosine triphosphate released by damaged cells may contribute to COVID-19 outcome [figures 3 and 4]. In addition to RIG-I, MDA5 and MAVS RNA viruses are also sensed by the stimulator of interferon genes (STING) that that is activated by cGAMP when enveloped RNA viruses interact with the host membranes (76). Downstream STING engages TBK1 that actives IRF3 and/or NFκB inducing type 1 IFN and/or proinflammatory cytokines. That hyperactivation of STING contributes to severe COVID-19 has been hypothesised by Berthilot and Lioti (77) who present several lines of evidence the strongest being that gain of function mutations of STING associated with hyperactivation of type I IFN induces the disease SAVI (STING-Associated Vasculopathy with onset in Infancy). Affected children with SAVI present with pulmonary inflammation, vasculitis and endothelial-cell dysfunction that mimics many aspects of COVID-19 (78). Furthermore, STING polymorphisms are associated with ageing-related diseases such as obesity and cardiovascular disease possibility explaining the impact of co-morbidities and development of severe COVID-19 (79). Also, in bats in which SARS-CoV-2 may have arisen, STING activation and thus consequently IFNβ is blunted (80), likely aiding viral replication and spread as observed in early SARS-CoV-2 infection in humans. That DAMPS released due to viral cytotoxicity may contribute to severe COVID-19 is best exemplified by HMBG1 released by damaged and dying cells as well as activated innate immune cells especially in sepsis (81). Depending on its conformation HMGB1 triggers TLR2, TLR4 and TLR9, the receptor for advanced glycation end-products (RAGE), and triggering receptor expressed in myeloid cells 1 (TREM-1) [figure 3]. In mice, intratracheal administration of HMGB1 activates mitogen-activated protein kinase (MAPK) and NFκB, inducing proinflammatory cytokines, activating endothelial and recruiting neutrophils in the lung – key pathological features of severe COVID-19 (81,82). HMGB1, and especially the platelet-derived source may play a crucial role in SARS-CoV-2 vascular damage since HMGB1-/- mice display delayed coagulation, reduced thrombus formation and platelet aggregation (83). Furthermore, blocking HMGB1 is beneficial in experimental lung injury and sepsis suggesting therapies targeting HMGB1 might also be beneficial in severe COVID-19 (84).