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).