Importance of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus Viral Components: A Comprehensive Review

In December 2019, an outbreak emerged in Wuhan, a city in China. The illness resembled infections of unknown viral origin, such as the previous severe acute respiratory syndrome associated with the coronavirus 2 (SARS-CoV-2) in 2002-2003 and Middle Eastern respiratory distress syndrome (MERS-CoV) 2012-2013 in Saudi Arabia. Coronaviruses (CoV) are enveloped positive-strand RNA viruses found in a host of animals and humans, which belong to the family Coronaviridae and subfamily Coronavirinae, the order of the nucleoside sequences [1-7]. Though rare, CoVs can mutate and cross animal-wildlife barriers, returning to perpetuate the public health crisis. Not much is recognized or clearly defined about their evolution yet. CoVs can cause a range of diseases, including minor upper respiratory infections in humans to severe lower respiratory infections and are often clinically identified. The treatment indicated for CoVs is unfortunately and only, based on symptomatic and supportive therapy, in addition to the use of traceable isolates with modest success [8-13].

The objectives of the review were to show details about the virus and its components and transmission. The selection of articles and journals was based on high ranked ones.

Epidemiology of SARS COV-2

The pandemic of novel coronavirus is a matter of international concern and in such situations, it is ultimately important to provide timely information regarding the virus and its spread. The epidemiology, source and genome of the SARS COV-2 virus are firstly elucidated. Then, the subsequent virus spread is linked to population movement [14-18].

The basic reproductive number is estimated to be around 3 and its confidence interval marks an overall risk assessment relative to the secondary attack rate. There is evidence that the population fatality rate may vary by admissible risk factors. Datasets of estimates are based on the exportation of cases outside Wuhan. During the second and third weeks of January 2020, the virus spread led to deaths and a vital increase in the number of confirmed cases detected and worldwide exportation. Efforts to cut off the spread of the disease led to a partially reduced growth rate. To date, the confirmed cases of SARS COV-2 have been escalating day by day in Hubei. The data show that self-sustained human-to-human transmission has not yet been established among regions outside the Wuhan area. But with increasing invasion, the proportion of human-to-human cases with good exposure history will continue to multiply [19-23].

Global Spread of the Virus

As of 22nd November 2020, SARS COV-2 was still spreading globally with a cumulative figure of 57,785,259 persons affected and 1,373,448 deaths reported. The spread of this virus is making it difficult for people to know who may be infectious, leading to questions about how transmission occurs. Studies have reported that patients infected with the SARS COV-2 virus can transfer the virus to people through respiratory droplets, close contact and air. The air transmission route has been highlighted as the major path leading to the SARS COV-2 virus spreading worldwide due to similarities in virus signatures detected in sewage and the virus identified in symptomatic SARS COV-2 patients, while the importance of fecal-oral transmission potential due to the exact fecal/anal existence of the asymptomatic viral shedding employed by SARS COV-2 remains largely unknown. Controversial studies have shown waterborne transmission to be possible [24-27]. There is limited body of studies on the transmission of the virus, which needs more future studies.

The proportion of confirmed cases per 100,000 population in the Americas, i.e., the incidence of cases, exceeds the proportion in every other region or country. The number of known cases of SARS COV-2 has increased substantially over time from almost zero in the very beginning of March to over 1.3 million by the end of the month, with the number of new cases growing at an exponential rate. Around 32,411 persons have died because of infection by the pandemic virus. The number of new deaths increased by 53% over the same time. Although the number of deaths increased rapidly, the rate of increase was slower than the rate of increase in the number of new cases. Consequently, the proportion of deaths decreased from 3.67% at the beginning of the month to 2.46% by the end of the month [28-31].

The disease has spread from eight countries, with new deaths confirmed in 42 of 50 countries, or 84% of all countries within the region. Over 99% of all deaths have been reported by two countries. Although the number of new deaths increased substantially, the rate of increase in the number of new deaths slowed down during much of the month. Even so, a sustained, exponential increase in the number of cases globally resulted in the deaths increasing enough to keep fatalities on an upward exponential trajectory for the next week. There was a two-day window that could have been used to slow the exponential increase in deaths and cases, only to be allowed to close. At this rate, Earth begins to run out of time to control the spread. Up to 80% and 90% of the global and United States populations, respectively, might have to be quarantined to control the spread and flatten the curve [32,33].

Clinical Manifestations and Complications

Over one year and a half after the emergence of severe acute respiratory syndrome coronavirus-2, well known as the SARS COV-2 virus, the world is still unable to answer many questions about this virus. It is reported that the clinical presentation of SARS COV-2 varies from no symptoms to severe complications and multiorgan failure. Therefore, knowing the various ranges of clinical symptoms and complications in patients with SARS COV-2 is essential for helping each patient as soon as possible and also for obtaining the appropriate measures to control and prevent the further disease [52-54].

The virus was initially discovered to cause severe pneumonia and subsequent case reports or series of patients have described atypical clinical phenotypes, other than respiratory system invasion. Multiple system organ failure and sepsis-like presentations have been reported. Patients with SARS COV-2 may present with extrapulmonary symptoms, including cutaneous findings, headache or dizziness, neurologic deficits, musculoskeletal symptoms, gastrointestinal complaints, loss of smell or taste and cardiovascular complications. In laboratory findings of SARS COV-2, it is reported that changes occur in various magnitudes such as leukopenia, leukocytosis, neutropenia, neutrophilia, hypocalcemia, hypokalemia, lymphopenia, lymphocytosis, thrombocytopenia, thrombocytosis, etc., besides increased indexes of infection [55-57].

Virology and Pathogenesis of SARS-COV-2

SARS-CoV-2 belongs to a family of viruses known as coronaviruses. It is an enveloped virus with a single-stranded RNA genome. It is a large virus with a genome size of about 30 kb. The genome has 14 open reading frames, with the four major structural proteins: the spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins at the 3 end of the genome. The positive-sense single-stranded viral genome is effectively translated into a long polypeptide, which is cleaved by viral proteases and host proteases into smaller proteins. It is the S protein, through the receptor binding domain, that is essential for binding to the ACE2 receptor and its priming by transmembrane serine protease 2 allows the virus to enter the host cell through membrane fusion with the host cell membrane. SARS-CoV-2 replicates mainly in the upper respiratory tract and spreads into the lower respiratory tract to infect type I and II pneumocytes and alveolar representative cells. The damage to the lungs appears to be the main cause of mortality from the virus, although there is now a recognized range of clinical phenomena that can occur over the course of infection. In addition to these effects, damage to other organs has been reported, including the kidney, liver and heart. The interplay between the SARS-CoV-2 virus and the host immune system is significant. The cytokine release syndrome has been shown to be one of the key factors in disease progression. Additionally, strong antibody responses and the presence of high neutralization activity could contribute to disease recovery [34-38].

Structure and Genome of the Virus

SARS COV-2 is an acute respiratory infectious disease. It is caused by the type of coronavirus SARS-CoV-2 that was first detected in the city of Wuhan, Hubei province, China and has spread rapidly across the world. The number of confirmed cases of SARS COV-2 has now reached almost 1,700,000. The virus is a cause of great concern because it has high morbidity and infectivity. In some cases, it can even be lethal. The structure and genome of the virus will be the starting point in finding the most effective measures to control and destroy the disease. For instance, the virus is composed of a spike-like glycoprotein corona, which is a unique morphological characteristic of the virus, but also the most important structure for its infectivity, providing multiple targets of antibodies for research. Genomes encode 6-11 structural proteins related to virus infection, assembly and release [39-42].

The origin and evolution of the SARS COV-2 virus have received a great deal of concern and attention. The virus is closely related to the genome sequence of six strains of highly homologous bat-derived coronavirus. In addition, the tract in the SARS COV-2 virus that is highly homologous to the pangolin coronavirus indicates the close species relation. Whereas the receptor-binding domain in the SARS COV-2 virus does not seem to be derived from the pangolin coronavirus. The virus invades the host primarily through a specific interaction between the corona spike glycoprotein and receptor protein and its high sequence homology is related to homology models, suggesting a high-risk mismatch in the receptor [43-45]. Only by clarifying the infection characteristics and pathogenic mechanisms of the SARS COV-2 virus and related proteins, to provide new targets for structure-based design or virtual screening of small molecular inhibitors, could the contagion be controlled and its harmfulness effectively minimized. Therefore, this paper provides the most recent state of structures and genomes of the current understanding of various research accomplishments and provides detailed information for the subsequent structural-functional research [46, 47] (Figure 1).

Figure 1: SARS COV-2 Virus pathogenesis

Mechanism of Infection

Coronaviruses contain the S (Spike) protein on the surface. The S-protein is a large type I spike glycoprotein that mediates the host cell receptor binding and membrane fusion processes. Both the S1 and S2 subunits are critical for viral infection, with the S1 subunit containing a receptor binding domain and the functional ganglioside binding sites. The S-protein is the most important determinant of host cell specificity, the site of host receptor binding and the distal position of glycosylation in many coronaviruses and other animal coronaviruses. Coronaviruses use glycosylated S-proteins to bind sialic acid receptors during the first steps of infection and internalization. The L protein is the largest subunit packed with RNA to synthesize new viral genomes and the second copies of viral proteins. Particles appeared as small, rounded S-protein-covered portions at the extracellular level. It has been reported that the nucleocapsid protein of some other coronaviruses is in the endoplasmic reticulum- Golgi intermediate compartment. Thus, the subcellular location of SARS COV-2 and other coronaviruses remains to be further studied [48,49].

In general, coronaviruses use endocytic pathways to enter the host cell after binding the receptors on the cellular surface. For instance, one coronavirus enters the host cell by clathrin-mediated endocytosis. The subgroups have not been widely studied, but a coronavirus belonging to a specific group has been found to use the clathrin-mediated endocytosis pathway. It is known that the early and late endosomes are involved in the entry of the virus into the host cell, after which the pH of the late endosome decreases. The fusion of the virus S-protein with the endosome membrane begins, which can be triggered by the reduced pH, mediating the release of viral RNA from the nucleocapsid protein into the cytosol. Conclusively, the virus hijacks the host to generate synthesized viral proteins and then replicate the complete virion forms. Subsequently, those virions release from host cells and become the transmission medium between hosts. The release mechanism of all coronaviruses depends on the complex interaction with host cell organelles and the virions' envelope, which is the above-mentioned endocytosis [50,51].

SARS COV-2 has been causing a lot of casualties and economic loss globally. Knowing the comprehensive symptoms of SARS COV-2 can help detect the disease timely and protect individuals around the patients. There are many suspected individuals, but not all of them can timely receive medical examination. At some points, the medical examination resources are very limited, which makes it even harder for people who are not feeling so bad to receive medical examination. At those times, it is very important to know the most typical SARS COV-2 symptoms and distinguish them from other common flu symptoms. Some of the common flu symptoms are sore throat, cough, runny nose, congestion, fever, fatigue, headache, muscle soreness and watery eyes [58, 59].

The symptoms of SARS COV-2 include fever, cough, chills, repeated shaking accompanied by chills, difficulty in breathing, muscle pain, headache, sore throat, new loss of taste or smell, nausea or vomiting, diarrhea and many other less common symptoms. Fever, dry cough and tiredness are commonly discovered and less likely common symptoms are aches and pains, sore throat, diarrhea, conjunctivitis, headache, loss of taste or smell, a rash on the skin, or discoloration of fingers or toes. Some cases can also be asymptomatic, which means infected people do not have symptoms. People of all ages who come into close contact with SARS COV-2 patients or people who have been to high-risk areas should be vigilant. Although any of the above symptoms may be mistaken for symptoms of common flu, SARS COV-2 symptoms usually start slowly and are often mild at the beginning. It is therefore very important to take everyday preventive actions to stay healthy and timely receive medical examination when patients don't feel well [60,61].

Severe Cases and Risk Factors

Most of the clinical cases suffered only mild respiratory symptoms and recovered, while those with severe and critical cases mainly presented as pulmonary toxicity with dyspnea and hypoxemia, especially via acute respiratory distress syndrome. Patients with severe cases were often elderly males with comorbidities, such as chronic obstructive pulmonary disease, diabetes, hypertension and malignancy. At the time of admission, severe cases were usually presented with respiratory failure and hypoxemia, while others were accompanied by elevated serum levels of D-dimer and decreased lymphocyte counts. It is worth mentioning that for elderly patients, especially men, smoking cessation and alcohol restriction should be suggested to protect themselves in advance. The severity of the disease in males was suggested to be related to the alcohol impact on ACE2, as alcohol could promote the activity of ACE2 [62, 63].

The statistically significant risk factors for patients with severe SARS COV-2 were analyzed, including age (>70 years or the cut-off value from the receiver operating characteristic curve), blood type A and coexisting chronic diseases or dysfunctions, including hypertension, diabetes, heart diseases and chronic renal impairment. Additionally, the ratio of hepatic enzymes, albumin and blood components in severe cases, such as an increase in D-dimer, especially meeting the criteria for disseminated intravascular coagulation, an increased number of neutrophils and a decrease in lymphocytes, would represent the prognosis of the patients. Therefore, it is recommended to adopt a combination of risk factor screening for the assessment of patients, especially those with severe and critical cases that require intensive interventions [64,65].

Diagnostic Methods

As an RNA virus, SARS-CoV-2 can be readily detected with standard reverse transcription polymerase chain reaction. Traditional rRT-PCR testing has shown its accuracy and reproducibility in detecting minority populations, which greatly reduces the risk of false-negative results. The method is very appropriate for centrally located, highly organized laboratories, though results can take up to 5-6 hours to become available. Recently developed techniques can be paired with RT-PCR detection to improve sensitivity, thereby allowing for faster and more accurate SARS COV-2 detection. In addition to certain technology, a series of innovative technologies for the rapid detection of SARS-CoV-2 has been developed [66]. Some experts have developed a series of isothermal approaches for SARS-CoV-2 detection, some of which show promise for scaling up to high levels of throughput. This method offers several advantages in terms of its ability to minimize the need for specialized personnel, reduce the time required for diagnostic testing and result in lower costs. While containment in certain locations is particularly difficult due to a lack of resources or suitable laboratory facilities, isothermal technology is ideally suited to field diagnostics, which can often expedite results and improve overall accuracy related to specific medical or public emergencies [67] (Figure 2). False positive results could be an issue here. Primers and techniques should be applied correctly to minimize errors.