Advanced Biochemistry

Snow Du

What do you need to know about COVID-19?

Started in December 2019, we have been living in COVID-19 pandemic for over a year, as of today, there are 154 million confirmed cases and 3.19 million deaths globally. This pandemic is unprecedented, and it has caused severe damage not only to human health but global economy due to months of countrywide quarantine. The urge of controlling the spread of pandemics becomes stronger and stronger, thus, in order to overcome the current difficult situation, knowing the causative agent is the essential first step.

The causative agent for this pandemic is SARS-CoV-2, the seventh coronavirus that’s known to infect people, and the third Betacoronavirus that causes epidemics in humans, the previous ones are SARS-CoV and MERS-CoV. SARS-CoV-2 was first isolated from the patients who were admitted to local hospitals and have been to the Seafood and Wet Animal Market due to mystery pneumonia. Thus, epidemiologically, the market could be seen as the origin of SARS-CoV-2. By comparing the SARS-CoV-2 sequence with other known human coronaviruses’, not many similarities were found, hence it was considered as a novel coronavirus. Interestingly, though comparing alone the genome sequence of SARS-CoV-2 to the previous epidemic coronaviruses’, SARS-CoV-2 and SARS-CoV fell into two different clades, which means that SARS-CoV-2 did not evolve directly from SARS-CoV, by only comparing the spike protein sequence of SARS-CoV-2 to SARS-CoV spike, it showed extreme similarities between the two spike protein, a hypothesis of that SARS-CoV-2 might the same cell-entry mechanism as SARS-CoV was made and later proved to be correct.

The cell entry mechanism, in other words, how the virus gets into your cell, for both SARS-CoV-2 and SARS-CoV is binding viral spike protein to a cellular membrane receptor Angiotensin-Converting Enzyme(ACE2). This is interesting, because, in a healthy condition, ACE2 does not act as a receptor but a peptidase, which is an enzyme that cuts peptides, yet for SARS-CoV-2 infection, ACE2 plays the role of the receptor which initiates that cell entry mechanism. Many therapeutics for viral diseases have the targets the cell entry, SARS-CoV-2 is no exception. However, due to its rapid replication, experts are still looking for other more conserved targets for therapeutics. As mentioned before, the receptor binding step is an essential step for SARS-CoV-2 to initiate the cell entry mechanism, the other important step is cell fusion, which is a step that actually takes the virus into the cell, before the fusion starts, two cleavages have to be made in order to prime the spike protein to initiate cell fusion, the proteins that do the job of cleaving is TMPRSS2 and furin, TMPRSS2 is a protease, a protein that cuts protein and furin is a protein that only cut a specific region that contains conserved amino acids motif in order to activate the target. From previous studies, blocking either one of the cleavage enzymes would effectively reduce the pathogenesis, that says, reduce the replication ability of the virus.

Globally, there are 10 vaccines that have been developed and approved. Three are inactivated vaccines including CoronaVac, BBIBP-CorV that are from China and one from India (BBV152); two are mRNA vaccines, BNT162b2 from multination and mRNA-1273 from the US, worth mentioning, both of the vaccines are developed by pharmaceutical corporations (Pfizer and Moderna); three adenovirus vaccines AZD1222 from the UK, Sputnik V from Russia, and Ad5-nCoV from China; one non-replicating viral vector vaccine JNJ-78436735 from US and Netherland developed by (Johnson&Johnson); last but not the least, peptide-protein(EpiVacCorona) vaccine from Russia1.

However, the nature of rapid replication of RNA viruses, and the lack of proofreading leads to a higher mutation rate of SARS-CoV-2. As of now (May 2021), there are four major variants have known including B.1.1.7(UK variant), B.1.135 (South Africa variant), P.1 (Brazil variant), and B.1.617 (India variant). All of the variants have shown one or more mutations, mainly substitutions at where the spike protein of SARS-CoV-2 binds to ACE2 receptor, which multiple studies have shown that these variants have an increase of affinity to ACE2 receptor and increase of infectivity. So far, the most concerning mutations are the ones located in the receptor-binding domain because they would have a direct or indirect effect on binding to the receptor, ACE2. The main concern for the experts is whether the immunity protection built from previous infection or vaccine would still be able to protect the population from these variants, the short answer would be yes, but with an abolished efficiency. That says, the vaccine-induced antibodies’ activity probably would not be high enough to fight the variants after a period of time, thus one or many boosters might be needed in the future as a form like a flu shot.

Showing below is a timeline for SARS-CoV-2 and relative events:

Note: variant information is from CDC official website, thus did not add India variant in the timeline.

References

  1. COVID-19 vaccine tracker. (n.d.). Retrieved May 2, 2021, from https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker

12 thoughts on “What do you need to know about COVID-19?

  1. Hi Snow, I really appreciate your website on COVID-19 and think that it was the best choice to make for your project given that we are still living through the pandemic it has caused! I’m sure that there were so many themes & topics you could have covered, but I suppose what I’m more curious about after reading is whether or not you have read much about why COVID affects individuals in many different ways. For example, I have heard that people with O-positive blood types are less likely to have severe symptoms of COVID – why is that? Is ACE2 involved? Why are children not as affected by COVID? Another part of your project that I enjoyed reading about was the page on the different variants. I am currently living in Europe where vaccine accessibility is scarce compared to the U.S., and it scares me to think how much more the virus could mutate over time as they estimate that it could take years for the population here to get fully vaccinated. It will be interesting (and scary) to see if and what new variants pop up as we race towards achieving herd immunity across the world.

    1. Hi Olivia! Thank you for your comment! To answer your first question, regarding whether the severeness of SARS-CoV-2 associates with blood type, I have to say there’s no uniform answer for this question. I’ve seen papers stated that type A people are having a greater risk of SARS-CoV-2 infection, but I also have seen paper saying that there’s no association due to the sample sizes from previous papers were not convinced. But in my opinion, I think there would be no significant association between the infectivity and blood type, the reason is that the infectivity of SARS-CoV-2 would be related with the cell-entry mechanism, and the differences between different blood types are decided by whether they have A or B antigens (made of glycoprotein that’s located on the surface of the red blood cell), since SARS-CoV-2 would only infect the cells that contain ACE2 receptor, which red blood cells are not one of them also, the glycoproteins on the red cells are not yet found to involve in the cell-entry mechanism, I would say there should not be any associations between blood type and infection rate.

      To answer your second question, ACE2 is an enzyme in a biomolecular system, so comparing to SARS-CoV-2 which is an RNA virus, the gene that encodes for ACE2 should not involve as frequently as viral RNA. However, I would say there could be mutations just like any other genes.

      The third question regarding why the children are less likely to have severe symptoms. To answer this question, we have to consider what are the factors that can cause severe symptoms: 1) prevalence of ACE2 receptor 2) immune protection system which causes inflammation. Therefore, here is some hypothesis that has been made to explain why children are less likely to have severe symptoms: 1) immunity differences, children’s innate immune system is much higher than adults’, thus it’s possible that children’s better immunity protects them from infecting 2) microbiota, since the ACE2 is translated almost everywhere in the organs throughout the body, children however have different oropharyngeal, nasopharyngeal, lung and/or gastrointestinal microbiota. Microbiota plays a role of regulation and inflammation control, thus, it could be another reason that children are less prone to infection because of the support from microbiota in the organs where ACE2 is most abundant at.

  2. On the page ‘SARS-CoV-2 Pre-fusion Cell Entry Mechanism’ you touched on the hypothesis that the ‘RRAR’ furin cleavage site is responsible for the higher transmissibility of the virus, and on the landing page that “blocking either of the cleavage enzymes could effectively reduce the replication of the virus.” Is this insertion sequence found in any other viruses and what mechanism of action enhances cell-cell fusion? I am also wondering, could furin be a potential target for preventing cell-cell fusion and inhibiting viral spread?

    1. Hi Alyssa, thanks for your comment! The short answer to your first question is yes, the RRXR motif is where furin cuts and the cleavage site is also found in multiple other viruses such as avian influenza virus haemagglutinin (HA), HIV-1, measles, respiratory syncytial virus (RSV), and most importantly, in MERS-CoV S. The reason it’s called novel is beceause SARS-CoV-2 is considered to have the same cell-entry mechanism as SARS-CoV, yet SARS-CoV does not contain such furin site. Therefore, in my opinion, evolutionarily, SARS-CoV-2 has adopted both of the previous epidemic coronaviruses’ characteristics to enhance its virulence.

      To answer your second question, yes, furin has been considered as a target for developing antiviral therapeutics. In the study here, the authors have shown that furin inhibitors (CMK and naphthofluorescein) and both of them have shown the effect on decreasing virus production, which can be considered as a promising therapeutic target!

      Hope I have answered your question!

  3. Great article! Were experts expecting vaccinations to be rolled out this quick? What was the biggest hurdle in that process?

    1. Hi Niko, thank you so much for your comment! To answer your first question, the experts originally were expecting to have a developmental duration of 18 months, the biggest driving force in my opinion for COVID vaccines to be able to roll out this quick is the funding. In 2020, 20 billion was granted for COVID-19 vaccine development, which the average cost for developing vaccines for non-epidemic is known to be 200 million to 500 million. Thus, more funding means more groups can participate in the research process, then the faster the vaccines can be developed. In addition, the collaboration between countries also is another factor that I can think of. For example, for the Pfizer vaccine, though it’s known to be developed by Pfizer Inc. in fact, the vaccine is co-developed with a German pharmaceutical company called BioNTech.

      To answer your second question, the biggest hurdle in my opinion for COVID-19 vaccine is to make sure the vaccine-induced immunity can defend the variants. Because the pandemic is still not over and it’s still going strong, then that means more mutations would be developed over time if the condition is not under control.

      Hope I answered your question!

  4. Great work! It is awesome that there is so much research about COVID-19 available so quickly! Have you looked into the changes in the publication/scientific collaboration process regarding COVID-19 research? If so, what are your thoughts on these changes— pros/cons? Since you have established structural similarities and similar mechanisms between SARS- CoV- 1 and SARS- CoV- 2 (e.g. spike protein structure, same binding subunit of S1, same target protein of ACE2, common cleavage site), why do you think antibodies effective in the immune response on SARS- CoV- 1 were not effective on SARS- CoV- 2?

    1. Hi Kelly, thank you for your comment! To answer your first question, yes there have definitely been collaborations in COVID-19 researches, such as the production of vaccines. Also, because China was the first country to successfully isolate SARS-CoV-2, the sharing of the information can also be counted as a form of collaboration. The benefit of collaborations as we can see now is the rapid development of vaccines. I do think it’s a great thing, because in my opinion, though the western side of the world has already collaborated often, the communication and understanding between the western and eastern world have not yet been fully established maybe because of the cultural or language barriers. However, COVID-19 studies have brought every researcher together and this is really great and I think this change might not only just be made during pandemics but after.

      To answer your second answer, I totally agree with you and I puzzled the same question too, However, though the overall structural characteristics between SAR-CoV-1 S and SARS-CoV-2 S are similar, from this paper, the most important ACE2 contacting amino acids in SARS-CoV-1 spike receptor-binding domain (RBD) have been mutated in SARS-CoV-2 which I think is the main reason that the antibodies which target the S RBD-ACE2 interface would not be able to neutralize SARS-CoV-2.

  5. Hi Snow, excellent job bringing together so much valuable information about COVID-19, it’s been so fascinating to see how quickly research has been conducted and conclusions about the virus have been reached. I find it so interesting, as you pointed out on your pages, how SARS-CoV-1 and SARS-CoV-2 come from different clades, and yet share so many similarities. Much like Olivia, I have been curious as to how and why the virus effects people so differently. In particular, obesity appears to be a major determining factor in terms of how debilitating the virus is for individuals. I was interested to see whether or not you came across any research related to obesity and COVID-19, and if there are any hypotheses in regards to the mechanism by which the virus impacts those with obesity differently from others. Thanks!

    1. Hi Matt, thank you for your comment. To answer your question, I apologize that I did not show the immune response to SARS-CoV-2, but here’s the link. And to summarize in words, the presence of SARS-CoV-2 activates the immune responses and causes cytokine storms which is a phenomenon that our own body attacks ourselves rather than fighting the virus that the causation of the severe SARS-CoV-2 infection in our bodies. As mentioned above, the cytokine storm is the result of immune responses, and the storm can be triggered by inflammatory factors such as TNFα, IL-1, IL-6, and IL-10. To connect this information with obesity, the inflammatory factors mentioned previously are actually the products of the lipid pathway that can be directly secreted by the fat tissues in our bodies. That says, the obese population who has a higher body fat rate than the average would secret more of those inflammatory factors which would overactivate the cytokine storm, and result in more severe conditions.

      Hope I answered your question!

  6. Hi Snow! Awesome job on the website…COVID-19 is a uniquely tricky disease to take on for this project given the rapidly evolving nature of our understanding, as I’m sure you figured out in your research! You did really nice work curating everything here.

    I was most interested in your delineation of the myriad emerging variants we continue to hear about. As you note, some of the existing variants appear to able to be managed through our existing vaccines, while the fate of others is less clear at the current time (i.e. the Brazilian and Indian variants). Given the existing vaccines stimulate a multivalent humoral response against epitopes in the RBD of the SARS-CoV-2, what is your impression of the balance that exists between the virus’s ability to mutate sufficiently for vaccine escape and the resultant infectiousness/contagiousness of a viral variant capable of doing so?

    Also, there appears to be a degree of sexual dimorphism with respect to disease outcomes between males and females with this virus (i.e. males die more frequently). Have you come across anything in your research that may provide a molecular foundation for this disparity?

    1. Hi Eli, thank you for your comment! In my opinion, the failure to control the spreading of the virus around the world is the main cause of the continuously emerging variants since more replication means more mutations, especially given that SARS-CoV-2 is an RNA virus. To compare with DNA viruses, RNA viruses replicate much faster and with lack of accuracy, in other words, RNA viruses have a rapid replication with many mutations. The newly evolved Indian variant and its subvariants (B.1.617, B.1.617.2, B.1.617.3)contain a couple of consistent mutations that are highly concerning. One that has been considered to be responsible for the higher transmissibility is L452R and another mutation point E484Q that might be responsible for improving the ability of vaccine escaping, which means that the variant would not be recognized by our vaccine-induced immunity. Worth mentioning that E484Q mutation has been found in the two previous variants (Brazilian and South African), L452R is a novel mutation exclusively to Indian variants. To conclude my point, I do think the variant has the capability to increase both of its transmissibility and ability to escape at the same time.

      To answer your second question, the hormonal activity differences between males and females especially the steroid hormones such as testosterone, estrogen, and progesterone would lead to different immune responses in the two sexes. Clinically, males are found to have more inflammatory factors which are the factors that can cause the body to attack itself rather than attack the viruses than females. In my opinion, hormonal regulation is definitely related to such sexual divergence in the respect of responses to SARS-CoV-2. I’ll do more research on how these two related to each other and get back to you.

      Hope I answered your questions!

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