Pathogenesis of COVID-19

Coronaviruses (CoVs) are a community of Nidovirales viruses that includes the Coronaviridae, Arteriviridae, Mesoniviridae, and Roniviridae families. CoVs are members of the Coronavirinae subfamily of the Coronaviridae family of the order Nidovirales, which consists of four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.

Viruses belonging to the Nidovirales order and are enveloped, non-segmented positive-sense RNA viruses. These all have exceptionally broad RNA viral genomes, with some viruses producing the world’s largest RNA genomes, up to 33.5 kilobase (kb) genomes. Coronaviruses (CoVs) associated diseases affect both humans and animals indiscriminately. During its course of disease respiratory, urinary, and hepatic systems, and even the central nervous system, may all be affected. The 2002/2003 SARS and 2012 Middle East respiratory syndrome (MERS) epidemics demonstrated the possibility of newly-emerging CoVs being transmitted from animal to human and human to human.

2019nCoV, also known as COVID-19, is a new coronavirus that developed abruptly in Wuhan, China, with an epidemic of unusual viral pneumonia and then spread to the rest of the world. Based on its phylogenetic connections and genomic architecture, COVID-19 is categorized as a Betacoronavirus. COVID19 has remarkably similar sequences to SARS-related coronaviruses (SARSr-CoV), and the virus employs ACE2 as the SARS-CoV entry receptor. The International Committee on Virus Taxonomy’s Coronavirus Research Group named SARS-CoV-2 after similar associations with SARS-CoV-2 and the virus that caused the SARS outbreak (SARS-CoVs).

Coronavirus structure and life cycle

The viral particle has a diameter of 60 to 100 nm and is round or oval in shape [PMID:32230900]. Coronaviruses have the largest genomes (up to 32 kb) of any known RNA virus, with G+C content ranging from 32% to 43%. In diverse coronavirus lineages, there are a varying number of minor ORFs between the separate retained genes (ORF1ab, pulse, shell, membrane, and nucleocapsid) and downstream to the nucleocapsid gene. The viral genome has particular features, such as a unique region of the N-terminal inside the protein spike. The genes encoding the key structural proteins, such as S, E, M, and N, are present in both coronaviruses in the 5′ to 3′ order.

A normal CoV genome has six ORFs. Except for Gammacoronavirus, which encodes 16 nsps (nsp116), the initial ORFs (ORF1a / b), which account for around two-thirds of the overall length of the genome. ORF1a and ORF1b are involved in a frameshift that results in the production of two polypeptides: pp1a and pp1ab. Virally encoded chymotrypsin-like protease (3CLpro) or main protease (Mpro) and one or two papain-like proteases transform such polypeptides into 16 nsps. CoV subgenomic RNAs (sgRNAs) are used to make both the basic and accessory proteins.

ORFs 10 and 11, found in the one-third of a genome around the 3′terminus, include four major structural protectins: spike (S), membrane (M), envelope (E), and nuclecapsid (N) proteins. In addition to these four basic structural proteins, different CoVs encode unique structural and accessory proteins such as HE, 3a/b proteins, and 4a/b proteins. These mature proteins play a variety of important roles in genome integrity and transcription.

Pathophysiology

Replication

SARS-CoV-2 is mostly spread by respiratory droplets, direct contact, and also high likelihood for fecal-oral infection. Primary viral replication is typically observed in the upper respiratory tract mucosal epithelium (nasal cavity and throat), following further proliferation in the lower respiratory tract and gastrointestinal mucosa, resulting in mild viremia. Usually infections are under control at this time and are asymptomatic. However, non-respiratory symptoms such as severe liver and heart damage, renal failure, and diarrhea have been reported in certain individuals, signifying multi-organ involvement.

Sars-CoV-2 (COVID-19) binds through its spike and allows COVID-19 to infiltrate and invade cells via ACE2 (angiotensin-converting enzyme 2). If the virus is to continue its entry into the cell after this initial stage, the spike protein must be activated by a protease enzyme. SARS-CoV-2 (COVID-19) uses the trans-Membrane Serine Protease 2 (TMPRSS2) protease, as does SARS-CoV. The activation of TMPRSS2 as a protease is required to bind the viral receptor (spike protein) to its cell ligand (ACE 2).

The virus reaches the cells and then release the viral RNA genome into the cytoplasm and is transmitted as a result of which the viral genome starts replicating in two polyproteins and structural proteins. In a membrane in the endoplasmic reticulum (Golgi) the freshly formed envelope glycoproteins are incorporated and the nucleocapsid is made up from a genomic RNA mixture with the nucleocapsid protein. In the endoplasmic Golgi intermediate compartment (ERGIC), viral particles then germinate. Finally, the viral particle vesicles combine to split the viral from the plasma membrane.

SARS-CoV-2 employs host protease enzymes to covalently bind sugars to asparagine side chains near the protein surface during viral replication. The S protein must be broken by proteases found in the host cell in order for fusion to occur. The host’s own peptide bond breaking proteases cleave the S protein at certain places, allowing for fusion. Furthermore, whether coronaviruses enter cells through the plasma membrane or endocytosis is primarily determined by the presence of proteases on target cells. The ability of the virus to cross species, for example, from bats to humans, is similarly determined by proteolytic cleavage of the S glycoprotein.

Immune Suppression

A number of non-structural proteins, including RNA-dependent RNA polymerase (RdRp), are also produced. When the virus penetrates the host cells, the viral genome is released as a single, positive RNA, which is subsequently converted into viral polyproteins by the host cell protein translation machinery. SARS-CoV and MERS-CoV will produce, then replicate, double-membrane vesicles lacking in PRRs, preventing their dsRNA from being identified by the host.

Non-Structural protiens of corona viruses and their function:

Humoral and cellular immunity

SARS-CoV-2 can be detected with adaptive immune responses (both T and B cells) one week after the onset of symptoms. These adaptive immune responses, like viruses and/or virus-infected cells, are extremely potent. T-cells have two critical roles. CD8+T-cells actively infiltrate and kill virus-infected cells, whereas CD4+T-cells regulate primate B-cells and CD8+T-cells, which produce cytokines to recruit immune cells.

T cell responses are severely impaired in individuals with SARS-CoV infection in the acute stage. In these cases, weaker T cell activation prolongs viral load duration. One reason for this weakening T cell response is altered dendritic (DC) cell maturation and lymphoid organ migration, because dendritic cells are required for T cell activation. MERS-CoV infection has resulted in a slight increase in the number of CD8 cells, although the activation patterns of CD4 + T cells in patients remain unstable. Despite the fact that this response has been compromised, convalescent patients acquire memory T cells that are specific to coronavirus. They can be seen in patients up to two years after they have recovered. This pro-inflammatory characteristic accelerates the illness.

Cytokine Storm

The initial onset of accelerated viral replication may result in massive epithelial and endothelial cell death and vascular leakage, promoting the release of excessive pro-inflammatory cytokines and chemokines. The prevalent immunopathologic syndrome of SARS-CoV-2, SARS CoV and MERS-CoV infections and mortality is Acute Respiratory Distress Syndrome (ARDS). One of the key pathways for ARDS is the cytokine storm, the deadly unregulated systemic inflammatory reaction arising from the release of vast amounts of pro-inflammatory cytokines (IFN-a, IFN-g, IL-1b, IL-6, IL-12, IL-18, IL-33, TNF-a, TGFb, etc.) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc.) from immune effector cells in SARS-CoV infection.

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