Mechanisms of SARS-CoV-2 Transmission and Pathogenesis

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marks the third highly pathogenic coronavirus to spill over into the human population. SARS-CoV-2 is highly transmissible with a broad tissue tropism that is likely perpetuating the pandemic. However, important questions remain regarding its transmissibility and pathogenesis. In this review, we summarize current SARS-CoV-2 research, with an emphasis on transmission, tissue tropism, viral pathogenesis, and immune antagonism. We further present advances in animal models that are important for understanding the pathogenesis of SARS-CoV-2, vaccine development, and therapeutic testing. When necessary, comparisons are made from studies with SARS to provide further perspectives on coronavirus infectious disease 2019 (COVID-19), as well as draw inferences for future investigations.

Keywords: COVID-19; SARS, SARS-CoV-2; coronavirus; severe acute respiratory syndrome.

Figure 1

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Lifecycle. The SARS-related coronavirus (SARS-CoV and SARS-CoV-2) lifecycle commences by binding of the envelope Spike protein to its cognate receptor, angiotensin-converting enzyme 2 (ACE2). Efficient host cell entry then depends on: (i) cleavage of the S1/S2 site by the surface transmembrane protease serine 2 (TMPRSS2); and/or (ii) endolysosomal cathepsin L, which mediate virus–cell membrane fusion at the cell surface and endosomal compartments, respectively. Through either entry mechanism, the RNA genome is released into the cytosol, where it is translated into the replicase proteins (open reading frame 1a/b: ORF1a/b). The polyproteins (pp1a and pp1b) are cleaved by a virus-encoded protease into individual replicase complex nonstructural proteins (nsps) (including the RNA-dependent RNA polymerase: RdRp). Replication begins in virus-induced double-membrane vesicles (DMVs) derived from the endoplasmic reticulum (ER), which ultimately integrate to form elaborate webs of convoluted membranes. Here, the incoming positive-strand genome then serves as a template for full-length negative-strand RNA and subgenomic (sg)RNA. sgRNA translation results in both structural proteins and accessory proteins (simplified here as N, S, M, and E) that are inserted into the ER–Golgi intermediate compartment (ERGIC) for virion assembly. Finally, subsequent positive-sense RNA genomes are incorporated into newly synthesized virions, which are secreted from the plasma membrane [6,8,11,12]. Figure generated with BioRender.

Figure 2

Proposed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission Routes. The ongoing COVID-19 pandemic has resulted in numerous accounts of different transmission routes between humans. Droplet transmission (>5 μm) is the most pronounced and heavily implicated mode of transmission reported during the pandemic. Direct contact spread from one infected individual to a second, naïve person has also been considered a driver of human-to-human transmission, especially in households with close interactions between family members. The contagiousness of SARS-CoV-2 after disposition on fomites (e.g., door handles) is under investigation, but is likely a compounding factor for transmission events, albeit less frequently than droplet or contact-driven transmission. Both airborne and fecal–oral human-to-human transmission events were reported in the precursor SARS-CoV epidemic but have yet to be observed in the current crises. Solid arrows show confirmed viral transfer from one infected person to another, with a declining gradient in arrow width denoting the relative contributions of each transmission route. Dashed lines show the plausibility of transmission types that have yet to be confirmed. SARS-CoV-2 symbol in ‘infected patient’ indicates where RNA/infectious virus has been detected [43,44,47., 48., 49.,57,59,60]. Figure generated with BioRender.

Figure 3

Clinical Symptoms of Coronavirus Infectious Disease 2019 (COVID-19). COVID-19 manifestations in humans have been described to incorporate multiple body systems with varying degrees of onset and severity. Both the upper respiratory tract and lower respiratory tract manifestations are often the most noticeable if a patient is not asymptomatic, in addition to systemic symptoms that are the most frequently reported regardless of disease severity. Red-highlighted signs/symptoms tend to be over-represented in severe patients, but common symptoms are also present in more advanced COVID-19. A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus symbol denotes where a live virus and/or viral RNA has been isolated. Abbreviation: ARDS: acute respiratory distress syndrome [37,46,48,66,139]. Figure generated with BioRender.

Figure 4

Key Figure. A Brief Overview of Lung Pathology in Patients with Coronavirus Infectious Disease 2019 (COVID-19). Following inhalation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the respiratory tract, the virus traverses deep into the lower lung, where it infects a range of cells, including alveolar airway epithelial cells, vascular endothelial cells, and alveolar macrophages. Upon entry, SARS-CoV-2 is likely detected by cytosolic innate immune sensors, as well as endosomal toll-like receptors (TLRs) that signal downstream to produce type-I/III interferons (IFNs) and proinflammatory mediators. The high concentration of inflammatory cytokines/chemokines amplifies the destructive tissue damage via endothelial dysfunction and vasodilation, allowing the recruitment of immune cells, in this case, macrophages and neutrophils. Vascular leakage and compromised barrier function promote endotheliitis and lung edema, limiting gas exchange that then facilitates a hypoxic environment, leading to respiratory/organ failure. The inflammatory milieu induces endothelial cells to upregulate leukocyte adhesion molecules, thereby promoting the accumulation of immune cells that may also contribute to the rapid progression of respiratory failure. Hyperinflammation in the lung further induces transcriptional changes in macrophages and neutrophils that perpetuate tissue damage that ultimately leads to irreversible lung damage. Recent evidence suggests that systemic inflammation induces long-term sequela in heart tissues [66,79,80,82,84,87,90,95]. Abbreviations: BALF, bronchoalveolar lavage fluid; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor-κB; RIG-I, retinoic acid-inducible gene I; STAT1/2, signal transducer and activator of transcription 1/2; STING, Stimulator of interferon genes. Figure generated with BioRender.

Figure 5

Evasion of the Pattern Recognition Receptor-Type I Interferon (PRR-IFN-I) Pathways by Coronaviruses (CoVs). A simplified schematic of the canonical IFN response after sensing RNA viruses. Viral nucleic acid is first recognized by PRRs (e.g., retinoic acid-inducible gene I; RIG-I) that perpetuate signal transduction through an adaptor complex on the mitochondrial (mitochondrial antiviral-signaling protein; MAVS) or endoplasmic reticulum (Stimulator of interferon genes; STING) membrane surface. Here, the PRR–adaptor interactions recruit kinases that converge into a large complex, leading to phosphorylation of interferon regulatory factor 3/7 (IRF3/7) and nuclear factor-κB (NF-κB), transcription factors that enter the nucleus and transcribe IFN genes. Type-I and type-III IFNs then signal in an autocrine or paracrine manner through the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 1 and 2 (STAT1/2) pathway, culminating in antiviral IFN-stimulated gene (ISG) transcription. Listed here are SARS-CoV (CoV), SARS-CoV-2 (CoV-2), and MERS-CoV (M-CoV) IFN-I antagonists, which render these viruses resistant to IFN responses. IFN-III is also implicated in exhibiting potent antiviral effects in lung/intestinal tissues, but the underlying evasion strategies of this pathway for these viruses are currently unknown. SARS-CoV proteins are highlighted in blue, while functions of SARS-CoV-2 and MERS-CoV proteins are highlighted in red and green, respectively. ? denotes that a SARS-CoV-2 protein bound a member of that signaling pathway in [122], but further work is necessary to confirm its immunological mechanism. SARS-CoV-2 proteins with * denotes functional conservation with SARS-CoV [93., 94., 95., 96.,98,100., 101., 102., 103., 104., 105., 106., 107.]. Figure generated with BioRender.