SARS-CoV-2 Pathogenesis and Treatment of COVID-19: History
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Dona Susan Mathew
,
Tirtha Pandya
,
Het Pandya
,
Yuzen Vaghela
,
Selvakumar Subbian

The Coronavirus disease-2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has significantly impacted the health and socioeconomic status of humans worldwide. Pulmonary infection of SARS-CoV-2 results in exorbitant viral replication and associated onset of inflammatory cytokine storm and disease pathology in various internal organs. At present, the pathological manifestations of acute and long-term COVID-19 and the underlying pathogenesis is not fully understood. Although currently used mRNA vaccines help to reduce the death among COVID cases, the protective effect is not long-lasting. Similarly, there is no targeted therapy available currently to cure COVID-19. Therefore, additional studies to understand the host-pathogen interactions are urgently needed to develop improved vaccines and therapeutic interventions to combat the current global COVID-19 pandemic.

  • epidemiology
  • pathogenesis
  • viral vector
  • nucleic acid vaccine
  • protein subunit

1. Clinical Features and Etiopathogenesis of SARS-CoV-2

SARS-CoV-2 primarily affects the respiratory system although other organs are also affected as disease progresses. Initially, respiratory tract infection-related symptoms, including fever, cough, sore throat, dyspnea, dizziness, and chest tightness were reported in the case series from Wuhan, China and this heterogeneity further expanded to acute respiratory distress syndrome (ARDS). Other symptoms observed were headache, generalized weakness, loss of smell and taste, as well as vomiting, diarrhea, body pain, and memory loss [1][2][3]. SARS-CoV-2 enters the human body by inhalation of virus particles mainly by respiratory aerosol droplets, which are produced when an infected person coughs, sneezes, talks, or even breathes heavily. These are also the primary modes of viral transmission. Other modes like direct contact with contaminated surfaces and fecal-oral routes have also been reported [4]. Upon entering the respiratory system, SARS-CoV-2 binds to the receptor, Angiotensin Converting Enzyme 2 (ACE2), present in epithelial and endothelial cells of the upper respiratory tract. ACE2 receptors are also present in other non-immune and immune cells present in various organs like the heart, brain, skeletal muscles, kidney, intestine, and endothelial cells. ACE2 is part of the Renin Angiotensin System (RAS), well known for circulatory homeostasis where it plays a major role in balancing the levels of Angiotensin II (AngII) and Angiotensin [1][2][5][6][7][8][9]. ACE2 is involved locally in multiple biological processes which include inflammation, angiogenesis, cell proliferation, memory, sodium and water reabsorption, thrombosis, and plaque rupture. Human ACE2 protein is a zinc metallopeptidase, which is a type I transmembrane glycoprotein and has a single extracellular catalytic domain that predominantly localizes at the plasma membrane. Primarily a membrane protein in its full length, it also exists in truncated soluble form with the role of the latter in COVID-19 unclear. The SARS-CoV-2 binds with membrane ACE2 receptors with strong affinity and the infected cells undergo conformational changes as soon as the virus fuses into cell membranes [10][11].
Apart from ACE2, studies have shown that ACE2 independent entry mechanisms do exist for SARS-CoV-2. The receptors involved include extracellular matrix metalloproteinase inducer CD147 (EMMPRIN), neuropilin-1 (NRP-1), dipeptidyl peptidase 4 (DPP4), AXL tyrosine-protein kinase receptor, and C-Type lectins, including CD209/L, CLEC4G, low-density lipoprotein receptor class A domain-containing protein 3 (LDLRAD3), and transmembrane protein 30A (TMEM30A). The impact of these alternative receptors on the ACE2-dependent SARS-CoV-2 entry is unclear [12][13][14]. Although SARS-CoV-2 primarily affects the lungs, studies have shown tissue damage and clinical symptoms in multiple organ systems like cardiovascular, gastrointestinal, neurological, musculo-skeletal, renal, ocular, endocrine, and cutaneous in humans [15][16][17]. There are four main proteins in SARS-CoV-2: the spike protein (S), membrane protein (M), Envelope protein (E), and Nucleocapsid protein (N). S protein plays a major role in the entry of viruses into humans [18]. The S protein consists of two subunits, S1 and S2. S1 helps in binding the receptor and S2 helps in the fusion of cell membranes [16]. As soon as the S1 subunit binds with the ACE2 receptor of the host cell, a transmembrane serine protease TMPRSS2 cleaves it from S2, which undergoes conformational change, and fuses with the host cell [19][20][21]. Alternately, in cells expressing low TMPRSS2, once engulfed into an endosome, SARS-CoV-2 escapes from the endosome by activation of their spike protein by cathepsins (non-specific low pH activated proteases) and further fusion of the host cell with viral membrane. In both mechanisms, the SARS-CoV-2 releases its RNA into the host cell cytoplasm, which translates to form two polyproteins that help in the formation of a replication translation complex in a double membrane vesicle. The viral RNA undergoes further replication to produce other accessory and structural proteins. All components then assemble and fuse with the cell membrane to release the virus. Complete virions capable of infecting other cells are assembled through the binding of N proteins to RNA molecules, which are then covered by E and M proteins [22]. Several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the N protein, can trigger inflammation while inhibiting host antimicrobial responses, such as delaying the onset of type I (IFNα, IFNβ etc.) and type III (IFN λ, IFNε etc.) interferon responses against viral infection [23]. Thus, hyperinflammation, in combination with the lack of effective antiviral responses against SARS-CoV-2 early on during infection, promotes disease progression that makes the patients succumb rapidly to COVID-19 [16]. Adaptive immune responses, mediated by both T cell (not-associated with antibodies but T- cell driven cytokines/chemokines) and B cells (associated with antibodies, such as IgG, IgA, IgM etc.) resulting in cell-mediated immunity and humoral immunity, respectively, were observed in COVID-19 [16].
The pattern recognition receptors (PRR) of the host cells recognize the viral entry and exert two major responses—one mediated by interferons type I and type III and its associated genes along with cytokine secretion and the second one by leukocytes along with associated chemokine secretion. The SARS-CoV-2 non-structural proteins (NSPs 10, 13, 14, 15, 16) help to shield the viral RNA and mimic host cell RNA to evade the PRRs. They also help avoid immune sensing besides triggering cytokine secretion. Dysregulation in the function of myeloid cells (dendritic cells), as well as innate lymphoid cells (NK cells), is observed in acute respiratory distress syndrome. In severe cases, there are increased numbers of neutrophils and monocytes, specifically cluster of differentiation 14/16 positive (CD14+CD16+) inflammatory monocytes, Granulocyte macrophage colony-stimulating factor positive (GM-CSF+), and interleukin 6 positive (IL-6+) monocytes, along with a marked reduction of T-cells. In severe and critical COVID-19 cases, the CD8+ and CD4+ T cell counts were significantly reduced which could be attributed to T-cell exhaustion and results in disease progression. Exhausted T-cell responses have been reported in viral infections and malignancies and usually emerge during chronic infections. SARS-CoV-2 elicits a strong B cell response as evidenced by the robust and rapid expression of various antibodies, including IgM, IgG, and IgA, soon after infection that can be detected in the blood sample of infected individuals [1][24][25][26].
Initial clinical studies of COVID-19 patients indicated that the severe and critically ill had high levels of cytokines, predominantly IL-2, IL-6, IL-10, interferon-gamma (IFN-γ) inducible protein 10 (IP10), monocyte chemoattractant protein 1 (MCP-1), GM-CSF, and tumor necrosis factor-alpha (TNF-α), along of lymphopenia. Pulmonary immune cell infiltrations indicated severe inflammation, failure of effective cellular immune response and a cytokine storm in the patients with severe COVID-19 [25][27][28]. In addition, severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Studies from current COVID-19 pandemics have thrown light on the host and viral responses in these RNA viruses [1][3][6][16][24].

2. Variants of SARS-CoV-2

The SARS-CoV-2 viral genome can undergo mutations that can alter the virus’ pathogenic potential and better adapt to the infected host. Even single nucleotide polymorphisms (SNPs) can generate variants of SARS-CoV-2, which can drastically affect the virus entry into host cells, evade the immune system, and modify its transmissibility, severity of clinical manifestation, neutralization by antibodies, and host response to treatment and vaccines. SARS-CoV-2 variants of concern (VOC) strains included alpha, beta, gamma, delta, epsilon, and omicron as classified by the WHO, and contained SNPs in the receptor binding domains (RBDs) of S proteins. All except gamma VOC had increased transmissibility, with omicron having an increased risk of re-infection [29]. In contrast, SARS-CoV-2 variants of interest (VOI) strains show less severity on all aspects of viral adaptation. The WHO has described eight VOIs namely epsilon, zeta, eta, theta, iota, kappa, lambda, and mu [29][30]. The SNPs in these VOCs and VOIs have been described previously [31][32]. The WHO has recently added XBB.1.5 and 1.16 as VOIs and new sub-lineages of omicron lineage strains, BA.2.75, CH 1.1 XBB 1.91, XBB 2.3, and BA 2.86 as Variants Under Monitoring (VUM) [33].

3. Treatment of COVID-19

Although multiple SARS-CoV-2 strains can cause COVID-19 with different levels of severity in humans worldwide, there are not many effective treatment options available. While Molnupiravir and Paxlovid are available as orally administrable drug, Remdesivir is prescribed for treating hospitalized COVID-19 patients. Paxlovid is a combination of Nirmatrelvir and Ritonavir. While Nirmatrelvir is a protease inhibitor, Ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent increases the concentration of Nirmatrelvir to target therapeutic range. However, with Paxlovid, dose adjustment is required for patients with mild to moderate renal or hepatic impairment. Both Remdesivir and Molnupiravir are nucleoside analog prodrugs that do not need stringent dose adjustment in patients with renal and hepatic impairment. Although studies have shown that the use of oral drugs greatly reduced hospitalization of patients and reduced death, the use of corticosteroids was recommended along with anti-viral drugs for patients with severe COVID-19 [34][35][36].
In addition to the chemical drugs, monoclonal neutralizing antibodies namely Bebtelovimab, Tixagevimab, Cilgavimab, Bamlanivimab, Casirivimab, Imdevimab, Etesevimab, and Sotrovimab are approved by the USA-FDA for use in the treatment of COVID-19. These monoclonal antibodies target the receptor binding domain (RBD) of the viral S protein to tackle the progression of SARS-CoV-2 infection into COVID-19 and neutralize SARS-CoV-2 entry by blocking its engagement with the host cell receptors, such as the ACE2 receptor. However, the antibody therapy requires intravenous administration under medical supervision and is specifically used for high-risk groups. Though they are administered at the recommended dose, the patients may run the risk of immune-mediated reactions due to reactions to antibodies or off-target effects [36][37][38].

This entry is adapted from the peer-reviewed paper 10.3390/biom13111565

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