The Molecular Mechanisms of SARS-CoV-2
Image credit: NIAID-RML
Humans are not totally defenceless against coronaviruses – we’d be wholly extinct if that were the case. As the infection mechanisms of coronaviruses continually evolve, our immune system matches it with its ingenious systems. In this article, we’ll build on the basis of SARS-CoV-2’s infection that we explored in Article 1, and delve deeper into the pathology that underlies our efforts in designing vaccines.
After SARS-CoV-2’s spike protein latches onto the ACE2 receptor on respiratory surface epithelial cells, the viral RNA will be sent into the cell’s cytoplasm, which was covered briefly in Article 1. This process is managed by the 2 segments of the spike protein – S1 and S2. The shapes of these proteins are responsible for the characteristic look of coronaviruses, with S1 forming the “club” on top of S2’s “stalk”. The two proteins combine to form many protrusions from the coronaviruses’ membrane. A part of the amino-acid sequence on S1 can bind to entry-point receptors like ACE2, and we call these the Receptor Binding Domains (RBDs). Meanwhile, membrane proteases with polar amino acids like serine can pull apart other proteins by using its -OH subgroup, for example the Transmembrane protease serine 2 (TMPRSS2) can cut up either the spike protein or ACE2 to facilitate binding. The S2 protein then changes shape and inserts the virus into the cell membrane, thus facilitating the insertion of viral self-replication proteins into the cell. There are a few ideas we can build on the spike proteins of SARS-CoV-2 (Acheson, 2011, pp. 187–199). Firstly, comparing SARS-CoV with SARS-CoV-2, the affinity of SARS-CoV-2’s RBD towards entry receptors is much higher (Tai et al., 2020, p.615), which may be a factor behind why SARS-CoV-2’s R0 is higher than SARS-CoV’s. Secondly, the shape formed by S1 and S2 is reminiscent of the coiled-coil structure, a protein motif that is seen in many other viruses. Structurally, due to the protein motif’s shape being common amongst other pathogens, coronaviruses can easily interchange spike proteins with other viruses, thus gaining the ability to infect different species of mammals.
It is evident that S proteins are prime targets for the immune system to stop SARS-CoV-2’s infection in its infant tracks. One of the main strategies to prevent the virus from entering any cell is to block the RBD of S1. In the Immune system, B cells can synthesise antibodies, which are small proteins that can latch on tightly to other proteins (the antigens). Although antibodies are effective and energy-efficient to mass produce, each antibody can only recognise one antigen. Moreover, each B cell can only produce one type of antibody. This means there needs to be a system where a large variety of B cells can be produced to prepare for all sorts of antigens, and that the required B cell can be efficiently located for every serious pathogenic invasion. The 1987 Nobel Prize in Medicine was awarded to the discovery of Somatic Hypermutation and Recombination: the genome of baby B cells have extremely high mutation rates, which allows them to produce a larger range of antibodies to target a larger range of antigens.
The variety of antibodies is also increased with the large number of possible random pairings between the building blocks of antibodies, just like how there can be many ticket combinations from a small set of numbers in the Mark 6 lottery; the recombinatorial exchanging of sequences between the building blocks of V, D and J chains can even create new sequences for building blocks, as if they were creating more numbers for the lottery. Further adaptation to the type of pathogen can be realised as the B cell is programmed to churn out different isotypes of antibodies for different classes of pathogens. Once the B cell with a corresponding antibody for the antigen of the invading pathogen is found, the immune response can be significantly amplified by the numerous roles of antibody – from neutralising pathogens to facilitating immune function. Therefore, it is essential to find the B cell with antibodies corresponding to the SARS-CoV-2 RBD antigen for this method of defence.
From data published by the WHO several days ago (“Draft landscape of COVID-19 candidate vaccines,” 2020), there are currently 36 candidate vaccines in clinical trials and 146 vaccines undergoing basic science research. Out of all these choices, we need to find an ideal vaccine that can be able to elicit an adequate immune response for 6 months after a single injection; and onward transmission must be reduced (Folegatti et al., 2020). The first research group to develop a recombinant vaccine to target RBDs was from a Chinese Research Team (Yang et al., 2020). Firstly, they used molecular tools to recombine the genes encoding SARS-CoV-2’s RBD into bacteria and proceeded to farm the bacteria in order to produce large amounts of the RBD protein. This protein was injected into mice and macaques to give their immune system some time to search for the B cells that could produce antibodies to respond. As the model organisms were infected, the vaccine was then able to increase levels of effective antibodies in the serum, yet they could not observe any betterment in survival. Although this method has been successfully used in the Hepatitis B and Human Papilloma Virus (HPV) vaccines, one reason for the lack of clinical success may be due to the limitations of producing a vaccine, as we cannot completely imitate the molecular signals of a virus. In a normal viral infection, Pathogen-associated molecular patterns (PAMPs) will be detected by the immune system. Without the PAMP, the communication between different immune cells underlying antibody production would not function totally. Therefore, PAMP-containing adjuvants have to be added to recombination vaccines. As immunologists gradually realised “dirty” (with adjuvant) vaccines function more effectively than “cleaner” (without adjuvant) ones, this has been named “the Immunologist's dirty little secret”. The adjuvant used in the above-mentioned vaccine was an Aluminium salt – and interestingly the exact molecular pathways by which these adjuvants function have not been completely elucidated. Therefore, we might get a better response if we try other novel adjuvants.
In this article, we’ve explored how the Spike protein serves as the entry mechanism of SARS-CoV-2, and how vaccines can be designed to exemplify the immune response against this process. In Article 4, we’ll explore how the virus replicates and other ways of immune function against SARS-CoV-2!
Bibliography
Acheson, N. H. (2011). Fundamentals of Molecular Virology (2nd ed.). Danvers, MA: Wiley. Draft landscape of COVID-19 candidate vaccines. (2020). Retrieved from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
Folegatti, P. M., Ewer, K. J., Aley, P. K., Angus, B., Becker, S., Belij-Rammerstorfer, S., Bellamy, D., Bibi, S., Bittaye, M., Clutterbuck, E. A., Dold, C., Faust, S. N., Finn, A., Flaxman, A. L., Hallis, B., Heath, P., Jenkin, D., Lazarus, R., Makinson, R., … Oxford COVID Vaccine Trial Group. (2020). Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet (London, England), 1–13. https://doi.org/10.1016/S0140-6736(20)31604-4
Tai, W., He, L., Zhang, X., Pu, J., Voronin, D., Jiang, S., … Du, L. (2020). Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cellular & Molecular Immunology, 17(6), 613–620. https://doi.org/10.1038/s41423-020-0400-4
Yang, J., Wang, W., Chen, Z., Lu, S., Yang, F., Bi, Z., Bao, L., Mo, F., Li, X., Huang, Y., Hong, W., Yang, Y., Zhao, Y., Ye, F., Lin, S., Deng, W., Chen, H., Lei, H., Zhang, Z., … Wei, X. (2020). A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature, 1–9. https://doi.org/10.1038/s41586-020-2599-8
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