FIGURE LEGENDS
Figure 1. SARS-CoV-2 structure and genome. A)SARS-CoV-2 is a positive-sense RNA enveloped virus with the spike (S),
membrane (M), envelope (E) proteins embedded in the lipid envelope,
while the nucleocapsid (N) protein is associated with the RNA.B) The 5’ end of the genome is comprised of ORFa/ab encoding 2
large polyproteins including the replicase protein crucial for
self-generation of the non-structural proteins (nsp) while ORFs 2-10
encode the viral structural proteins (S, M, E and N) and accessory
proteins. C) The homotrimers spike proteins of 8-12 nm length
are heavily decorated with N-glycans moieties that can be recognised by
antibodies, C-type lectins and mannose binding proteins that aid viral
attachment to permissible cells, activate the complement system and may
be recognised by macrophages and antibodies (D).
Figure 2. SARS-CoV-2 subversion of interferon pathways.SARS-CoV-2 infects permissible cells via the angiotensin converting
enzyme two (ACE2). Following infection (A) the virion or viral
RNA is sensed by either the cGas/STING pathway where stimulator of
interferon genes (STING) engages TBK1, or via retinoid inducible gene I
(RIG-I) and melanoma differentiation-associated gene 5 (MDA5). These
pathways lead to activation of IRF3 and/or NFkB inducing type I/III IFN
that is recognised by IFN receptors (B) and subsequent
induction of the interferon stimulated genes (ISGs) and proteins many of
which have potent antiviral activities. Based on the knowledge of other
coronaviruses especially SARS-CoV, and emerging data from SARS-CoV-2
many of the non-structural, structural and accessory protein subvert and
inhibit numerous steps in these pathways thereby inhibiting IFN
production allowing increased viral replication.
Figure 3. SARS-CoV-2 activates innate immune pathways.SARS-CoV-2 infects permissible cells via the angiotensin converting
enzyme two (ACE2) and is taken by in the endosome where the virus is
recognised by Toll-like receptor 7/9 triggering MyD88 pathway, or TLR 3
via the TRIF pathway (A). PAMPS and DAMPS are also recognised
by TLR4 (B) or RAGE (C) triggering HMGB1induced damage
and (D) NLRP3 inflammasome activation. During viral replication
ORF3a and E proteins form viroporins that augment ROS production and
inflammasome activation.
Figure 4. SARS-CoV-2 is a vascular and coagulation disease.A) Binding of SARS-CoV-2 to ACE2 blocks ACE2-induced formation
of antioxidant angiotensin, facilitating oxygen free-radical formation.
Infection in some people also triggers pyroptosis, complement activation(B) and hyperinflammation with influx of macrophages, NK cells
and neutrophils (C). This self-augmenting cycle triggers
further cell damage and DAMPS and PAMPs release as well as ROS
production. D) Activation of neutrophils induces neutrophil
extracellular traps (NET) aided by the N protein and generated in
response to ROS-induced endothelial cell damage. Disruption of the
vascular barrier and endothelial cell exposure to proinflammatory
cytokine and ROS increases expression of P-selectin, von Willebrand
factor (vWF) and fibrinogen, that attract platelets triggering
expression of tissue factor. Together this sequence activates the
complement system, one of many pathways that crucially activates the
coagulation cascade leading to thrombi formation.
Suppl Figure 1. Replication Cycle of SARS-CoV-2 . Based on
knowledge emerging from the SARS-CoV-2 infection and other
coronaviruses, the cycle comprises of viral binding to the host cell via
ACE-2 (1) and virion uptake into the endosome. (2) The positive stranded
RNA allows direct translation of the genome (which is capped by nsp –
see text for details) generating the replicase polyprotein and
subsequent viral proteins some of which are necessary to form the double
membrane vesicles (DMV) (3). The replicase polyprotein enzyme
synthesises the negative strands to transcribe the small subgenomic
positive RNAs (4). These are used to produce the other viral proteins
(N, S,M and E and accessory proteins) and the positive RNA strands for
the new virions. The nucleocapsid protein binds to the RNA. The S, M and
E proteins are incorporated in the lipid envelope in the ER. The new
virons assemble in the ER-Golgi intermediate compartment (ERGIC) and
exocytosed in the Golgi complex (6). Finally, mature SARS-CoV-2 virions
are released from the host cell (7).