Host-pathogen interaction in COVID-19: Pathogenesis, potential therapeutics and vaccination strategies

Abstract

The current coronavirus pandemic, COVID-19, is the third outbreak of disease caused by the coronavirus family, after Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome. It is an acute infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This severe disease is characterised by acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Currently, no drugs or vaccines exist against the disease and the only course of treatment is symptom management involving mechanical ventilation, immune suppressants, and repurposed drugs. The severe form of the disease has a relatively high mortality rate. The last six months have seen an explosion of information related to the host receptors, virus transmission, virus structure-function relationships, pathophysiology, co-morbidities, immune response, treatment and the most promising vaccines. This review takes a critically comprehensive look at various aspects of the host-pathogen interaction in COVID-19. We examine the genomic aspects of SARS-CoV-2, modulation of innate and adaptive immunity, complement-triggered microangiopathy, and host transmission modalities. We also examine its pathophysiological impact during pregnancy, in addition to emphasizing various gaps in our knowledge. The lessons learnt from various clinical trials involving repurposed drugs have been summarised. We also highlight the rationale and likely success of the most promising vaccine candidates.

Keywords: Anti-virals; COVID-19; Co-morbidities; Life-cycle; Pathophysiology; Pregnancy; SARS-CoV-2; Vaccine.

Graphical abstract

Fig. 1

Genomic and molecular characteristics of SARS-CoV-2 virus. A. The genome of SAR-CoV-2: large positive sense, single-stranded, non- segmented RNA genome of 29,903 nucleotides in length. Two open-reading frames (ORFs), ORF1a and ORF1b code for non-structural proteins (nsps). The sgRNA code for the structural proteins, viral spike protein (S), envelope protein (E), membrane protein (M), and nucleocapsid protein (N), as well as several putative accessory proteins (3a, 6, 7a, 7b, 8, and 10). L: Leader 3′ sequence. UTR: 5′ untranslated region. B. Structure of SARS-CoV-2 viron: An enveloped virus containing the major surface antigens including, hemagglutinin-esterase (HE) and the spike (S) protein trimer, surrounding the genomic RNA that has been packaged in the nucleocapsid (N). C. Protein structure of the spike (S) protein monomer showing the key molecular domains involved in pathogenesis. D. Primary cellular host receptor and co-receptor for SAR-CoV-2. 1) Attachment and entry of SAR2- CoV-2 requires priming by transmembrane serine protease 2 (TMPRSS2) which cleaves the S protein into S1 and S2 portions, facilitating 2) S1 targeting and binding of the receptor angiotensin-Converting Enzyme 2 (ACE2), followed by receptor-mediated endocytosis of the virion into the host cell.

Fig. 2

Co-expression of ACE2 and TMPRSS2 in Respiratory Airways. TMPRSS2 is the key protease involved in priming SARS-CoV-2, which forms a receptor-protease complex with ACE2 on the host cell surface, thus facilitating viral targeting and entry to the host cell. Co-expression of ACE2 and TMPRSS2 has been found in proximal as well in distal airways. The nasal cavity has the highest expression of both the receptors in ciliated and secretory (goblet) cells compared to lung bronchi (ciliated and secretory cells) and lung parenchyma (alveolar type 2 progenitor cells, AT2).

Fig. 3

Affinity of Receptor Binding Domain (RBD) of Spike protein for ACE2. Structural conformation of receptor-binding domain (RBD) present in S1 region of SARS-CoV-2 spike protein is capable of influencing the ACE2-binding affinity. In case of SARS-CoV-2, the RBD contains a four-residue motif glycine- valine/glutamine-glutamate/threonine-glycine which enables the binding loop to take a different conformation. It can undergo two possible conformational changes, a “lying down state” which has low affinity towards ACE2 and a “standing up state” with high binding affinity. SARS-CoV-2 RBD is found mostly in lying down state, and thus being less accessible to ACE2. This hidden conformation of RBD in the spike protein can possibly be a masking strategy for immune evasion by SARS-CoV-2.

Fig. 4

SARS CoV-2 Life cycle. (1) The SARS-CoV-2 binds to the cell via the ACE2 receptor using the S1 subunit of the spike protein. Once bound, the S2 subunit facilitates virus-cell membrane fusion by two tandem domains, heptad repeats 1 (HR1) and heptad repeats 2 (HR2) to form a six-helix bundle (6-HB) fusion core, bringing viral and cellular membranes into close proximity for fusion and infection. (1b) Cathepsin B/L may also facilitate endosomal entry of the virus in TMPRSS2⁻ cells. (Yang and Leibowitz, 2015) Post fusion, the virus releases its 30 kilobase (kb) positive sense single stranded RNA (ssRNA) into the host cytoplasm. (Columbus et al., 2020) Using the host ribosomal machinery, the 5′ end of the ssRNA is translated into a viral poly-protein. (4a) The poly-protein is auto-proteolytically cleaved by virus-encoded proteinases into 16 non-structural proteins that form the (4b) replicase-transcriptase complex, which includes multiple enzymes like the viral RNA-dependent RNA polymerase and endo- and exonucleases essential for nucleic acid metabolism. (5a) The 3′ end of the genome expressing 13 ORFs and encoding the four major viral structural proteins: Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N) are also expressed using host ribosomal machinery. (5b) Concurrently, the ssRNA undergoes replication using viral RNA-Dependent RNA Polymerase. (Zhu et al., 2020a) S, E, and M structural viral proteins are then inserted into the endoplasmic reticulum (ER). (7a) These proteins then move to the ER-Golgi intermediate compartment via the secretory pathway. (7b) The viral RNA encapsulated by N protein buds into membranes of the ER-Golgi intermediate compartment. (Hu et al., 2017) The N protein encapsulated viral RNA and the S, E, and M structural viral proteins are assembled together to form a mature virion. (World Health Organisation, 2004) Following assembly, virions are transported to the cell surface in vesicles. (Widagdo et al., 2019) The SARS-CoV-2 virions fuse with the plasma membrane of the host cell for exocytosis; a large number of virions are released.

Fig. 5

Pathophysiology orchestrated by SARS-CoV-2. Type II pneumocytes infected with SARS-CoV 2 trigger the release of cytokines, chemokines and interferons. The secreted inflammatory mediators recruit macrophages, neutrophils and activated T cells. The stimulated macrophages secrete IL-1, IL-6 and TNF-α. This increases capillary permeability, causing plasma to leak into the interstitial space and the alveolus. The stimulated neutrophils release reactive oxygen species and proteinases, which destroy infected cells. The cell debris and the plasma combine to form a protein-rich fluid. The increasing fluid leads to dyspnoea and pneumonia. It also dilutes the surfactant lining of the alveolus causing alveolar collapse, which leads to hypoxaemia and acute respiratory distress syndrome. The sustained inflammation leads to systemic inflammatory response syndrome, which develops into septic shock causing multi-organ failure and death.

Fig. 6

Vaccine strategies for COVID-19. (a) Viral peptide sequences can be constructed into potential epitopes with possible immunogenic capabilities to be used as a vaccine against SARS-CoV-2. (b) RNA-based vaccines such as mRNA-1273 and BNT162, which contain mRNA coding for the spike protein of SARS-CoV-2. These are often encased inside lipid vesicle. (c) DNA-based vaccine such as INO-4800 expresses variants of SARS-CoV-2 spike protein that are often inserted into cells through electroporation. (d) PiCoVacc is an inactivated virus vaccine candidate which contains purified SARS- CoV-2 virus inactivated by β-propiolactone. (e) Viral vector vaccine such as ChAdOx1-nCov19 and Ad5-nCoV are usually genetically engineered adenovirus (replication-defective) which are capable of producing SARS-CoV-2 spike protein once inside the host. (f) Once the vaccine is inside the host, antigen presenting cells (APCs) such as macrophages (MΦ) and dendritic cells engulf the virus or the proteins translated by the viral genome. SARS CoV-2 viral peptide expressed on the surface of APCs are presented to T helper (Th) cells, which further activate B cell and cytotoxic T cells (Tc). B cells secretes antibodies specific to viral S- protein which further neutralizes the virions and other viral proteins. Tc cells mount cytolytic immune response to destroy virus-infected host cells. Memory B and T cells production can further provide immunity to the host.