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Biological Mechanisms of Coronavirus

By March 27, 2020 No Comments

The novel coronavirus (COVID-19, also known as SARS-CoV-2) has been identified as the cause of the current outbreak of respiratory illness in Wuhan, Hubei Province, China beginning in December 2019. As of March 22, this epidemic has spread to 195 countries across the world with over 375,000 confirmed cases, including 16,525 deaths (1). Due to the highly contagious nature of COVID-19, the World Health Organization has declared it a public health emergency of international concern. COVID-19 belongs to a family of viruses that can cause various symptoms, such as pneumonia, fever, shortness of breath, and lung infection. These viruses are common in animals worldwide, but very few cases have been known to affect humans (2). The emergence of COVID-19 marks the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 (3). Although it is still too early to predict susceptible populations, early patterns have shown a trend similar to the SARS-CoV and MERS coronaviruses. Susceptibility seems to be associated with age, biological sex, and other health conditions (2).  

COVID-19 is one of many coronaviruses, a group of enveloped positive-sense RNA viruses that are characterized by club-like spikes that project from their surface and an unusually large RNA genome (approximately 30 kilobases). Coronaviruses are divided into four genera,  alpha, beta, gamma and delta. Alpha and beta coronaviruses are able to infect mammals (COVID-19 is a beta coronavirus), while gamma and delta coronaviruses tend to infect birds (4).  

It is clear now that COVID-19 uses the angiotensin-converting enzyme 2 (ACE2), the same receptor as SARS-CoV to infect humans (3). Structural studies have shown that although the receptor binding domain (RBD) of COVID-19 may bind human ACE2 with high affinity, this interaction is not ideal and the RBD sequence is somewhat different from that shown in SARS-CoV to be optimal for receptor binding (5). Thus, the high-affinity binding of the COVID-19 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that COVID-19 is not the product of purposeful manipulation. Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for beta coronaviruses would have been used. However, the genetic data irrefutably shows that COVID-19 is not derived from any previously used virus backbone (5). 

The most plausible explanation for the origin of COVID-19 is natural selection in an animal host before zoonotic transfer into the first human host. As many early cases of COVID-19 were linked to the Huanan Market in Wuhan, it is very possible that the animal source was present at this location. Given the similarity of COVID-19 to bat SARS-CoV-like coronaviruses, it is also likely that bats serve as reservoir hosts for its progenitor. Additionally, Malayan pangolins illegally imported into the Guangdong province contain coronaviruses similar to COVID-19, and may also be an animal source (5). Although the RaTG13 bat virus remains the closest to COVID-19 across the genome, some pangolin coronaviruses exhibit strong similarity to COVID-19 in the RBD, specifically (5).  

As an emerging acute respiratory infectious disease, COVID-19 primarily spreads through the respiratory tract, by droplets, respiratory secretions, and direct contact. The ACE2 protein presents in abundance on lung alveolar epithelial cells and enterocytes of the small intestines (3). In order to infect, the virion S-glycoprotein on the surface of COVID-19 attaches to the ACE2 receptor on the surface of human cells. The S glycoprotein includes the RBD. After membrane fusion, the viral genome RNA is released into the cytoplasm, and the uncoated RNA translates two polyproteins, pp1a and pp1ab, which encode non-structural proteins, and form the replication-transcription complex (RTC) in double-membrane vesicles. Continuously, the RTC replicates and synthesizes a nested set of subgenomic RNAs, which encode accessory proteins and structural proteins. Mediating endoplasmic reticulum (ER) and Golgi, newly formed genomic RNA, nucleocapsid proteins and envelope glycoproteins assemble and form viral particle buds. Lastly, the virion-containing vesicles fuse with the plasma membrane to release the virus (3). The most commonly reported symptoms following COVID-19 infection are fever, cough, myalgia or fatigue, pneumonia, and complicated dyspnea. Patients with mild symptoms have been reported to recover after one week, while severe cases are reported to experience progressive respiratory failure due to alveolar damage from the virus, which may lead to death. Cases resulting in death have been primarily middle-aged and elderly patients with pre-existing diseases (tumor surgery, cirrhosis, hypertension, coronary heart disease, diabetes, and Parkinson’s disease) (2). 

References  

  1. COVID-19 CORONAVIRUS PANDEMIC. (n.d.). Retrieved March 22, 2020, from https://www.worldometers.info/coronavirus/ 
  1. Adhikari, S., Meng, S., Wu, Y. et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty 9, 29 (2020). https://doi.org/10.1186/s40249-020-00646-x 
  1. Guo, Y., Cao, Q., Hong, Z. et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Military Med Res 7, 11 (2020). https://doi.org/10.1186/s40779-020-00240-0 
  1. Fehr, A. R., & Perlman, S. (2015). Coronaviruses: an overview of their replication and pathogenesis. Methods in molecular biology (Clifton, N.J.), 1282, 1–23. https://doi.org/10.1007/978-1-4939-2438-7_1 
  1. Andersen, K.G., Rambaut, A., Lipkin, W.I. et al. The proximal origin of SARS-CoV-2. Nat Med (2020). https://doi.org/10.1038/s41591-020-0820-9