Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage

Abstract

Innate immune sensing of viral molecular patterns is essential for development of antiviral responses. Like many viruses, SARS-CoV-2 has evolved strategies to circumvent innate immune detection, including low cytosine-phosphate-guanosine (CpG) levels in the genome, glycosylation to shield essential elements including the receptor-binding domain, RNA shielding and generation of viral proteins that actively impede anti-viral interferon responses. Together these strategies allow widespread infection and increased viral load. Despite the efforts of immune subversion, SARS-CoV-2 infection activates innate immune pathways inducing a robust type I/III interferon response, production of proinflammatory cytokines and recruitment of neutrophils and myeloid cells. This may induce hyperinflammation or, alternatively, effectively recruit adaptive immune responses that help clear the infection and prevent reinfection. The dysregulation of the renin-angiotensin system due to down-regulation of angiotensin-converting enzyme 2, the receptor for SARS-CoV-2, together with the activation of type I/III interferon response, and inflammasome response converge to promote free radical production and oxidative stress. This exacerbates tissue damage in the respiratory system, but also leads to widespread activation of coagulation pathways leading to thrombosis. Here, we review the current knowledge of the role of the innate immune response following SARS-CoV-2 infection, much of which is based on the knowledge from SARS-CoV and other coronaviruses. Understanding how the virus subverts the initial immune response and how an aberrant innate immune response contributes to the respiratory and vascular damage in COVID-19 may help to explain factors that contribute to the variety of clinical manifestations and outcome of SARS-CoV-2 infection.

Keywords: COVID-19; SARS-CoV-2; endothelia; immunology; inflammation.

Fig. 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 open reading frame (ORF)a/ab encoding two 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 recognized 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).

Fig. 2

SARS‐CoV‐2 subversion of interferon (IFN) pathways. SARS‐CoV‐2 infects permissible cells via the angiotensin‐converting enzyme 2 (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 (MDA‐5). These pathways lead to activation of IFN‐regulatory factor (IRF3) and/or nuclear facror kappa B (NF‐kB) inducing type I/III IFN that is recognized by IFN receptors (b) and subsequent induction of the IFN‐stimulated genes (ISGs) and proteins, many of which have potent anti‐viral 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.

Fig. 3

SARS‐CoV‐2 activates innate immune pathways. SARS‐CoV‐2 infects permissible cells via the angiotensin‐converting enzyme 2 (ACE2) and is taken by in the endosome where the virus is recognized by Toll‐like receptors 7/9 triggering the myeloid differentiation primary response 88 (MyD88) pathway, or Toll‐like receptor (TLR)‐3 via the TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF) pathway (a). Pathogen‐associated molecular patterns (PAMPS) and damage‐associated molecular patterns (DAMPS) are also recognized by TLR‐4 (b) or receptor for advanced glycation end (RAGE) (d) triggering high mobility group box 1 (HMGB1)‐induced damage and NOD pyrin domain‐containing 3 (NLRP3) inflammasome activation. During viral replication ORF3a and E proteins form viroporins that augment reactive oxygen species (ROS) production and inflammasome activation.

Fig. 4

SARS‐CoV‐2 is a vascular and coagulation disease. (a) Binding of SARS‐CoV‐2 to angiotensin‐converting enzyme 2 (ACE2) blocks ACE2‐induced formation of anti‐oxidant angiotensin, facilitating oxygen free‐radical formation. Infection in some people also triggers pyroptosis, complement activation (b) and hyperinflammation with influx of macrophages, natural killer (NK) cells and neutrophils (c). This self‐augmenting cycle triggers further cell damage and damage‐associated molecular patterns (DAMPS) and pathogen‐associated molecular patterns (PAMPS) release, as well as reactive oxygen species (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.