We are a group of scientists from the Biochemistry department at Lund University, Sweden. We are interested in understanding structure and function of different biological molecules including viruses. Currently we are holding journal reading clubs where we try to learn more about SARS-CoV-2 virus, or the "new corona virus".
As scientists we have capability and responsibility to analytically read, discuss and share our thoughts with a broader audience and we therefore created this webpage and we plan to update regularly. We will do our best in understanding and interpreting results from scientific papers we read. However we cannot have a full insight into quality of performed research. When one tries to summarize the information from scientific literature, it is not always possible to include all details and the authors conclusions might be misinterpret.
We hope that this resource can answer some questions related to coronaviruses, and explain the scientific literature that we have read so that those of you who are not scientists can get some of the information that they supply.. We will format this page in question and answers schemes and we will always provide reference to the original source.
Q1: What is coronavirus?
A1: Coronaviridae is a family of viruses that cause disease in humans or other animals. Coronaviruses cause a range of diseases from common colds to Severe Acute Respiratory Syndrome (SARS) and Covid-19. Like other viruses the coronaviruses need to hijack host cells from another organism in order to replicate. The virus particles need a way to enter the cells of the host and then the host cell is used to replicate the viral genome and produce more virus particles. Coronaviruses are so called enveloped viruses. Their core which contains their genetic material, RNA, is surrounded by a lipid membrane held together by envelope proteins. On the surface, the coronaviruses have a protein called the spike protein which they use to recognize and bind to host organism cells in order to penetrate the cells and use their machinery to replicate.(https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/virus-replication) (https://mmbr.asm.org/content/62/4/1171), (https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0)
Q2: How many corona viruses haven been discovered?
A2: Many coronaviruses have been discovered. The family Coronaviridae contains 3500 species that scientists have sequenced the complete genome of. However SARS-CoV-2 is only the seventh coronavirus known to infect humans The most known coronaviruses are the variants that have caused recent epidemics. Severe Acute Respiratory Syndrome (SARS) spread to several countries in 2002-2003 was caused by the virus called SARS-CoV, Middle Eastern Respiratory Syndrom (MERS) spread in 2012 was caused by the virus MERS-CoV. There is also HKU1, NL63, OC43 and 229E which can infect humans but are associated with mild symptoms. The current pandemic of Covid-19 is caused by the virus SARS-CoV-2.(https://www.viprbrc.org/brc/home.spg?decorator=corona), (https://www.nature.com/articles/s41591-020-0820-9)
Q3: What is the origin of human coronaviruses MERS-CoV, SARS-CoV and SARS-CoV-2 (Covid-19 virus)?
A3: Human coronaviruses MERS-CoV and SARS-CoV originates most likely from bats and were transmitted to humans via camels and civets. Other human coronaviruses have originated from bats or rodents and have been transmitted through intermediate organisms to humans. The "new coronavirus" SARS-CoV-2 we don't yet know the origin of but it has been found that it has great similarity with a variant that is found in bats. We also don't know if there is other intermediate organisms involved in transmission to humans.
It is improbable that SARS-CoV-2 in man-made. Its receptor-binding domain (RBD), responsible for the binding to cells, is optimised for human binding with a very different solution from those previously predicted. Moreover, if SARS-CoV-2 was man-made a virus backbone would have been used to create this virus. However, genetic data shows clearly that SARS-CoV-2 is not derived from any previously used virus backbone (https://www.nature.com/articles/s41579-018-0118-9er) (https://www.nature.com/articles/s41586-020-2179-y) (https://www.ncbi.nlm.nih.gov/pubmed/20567988) (https://www.nature.com/articles/s41591-020-0820-9)
Q4: Does SARS-CoV-2 require intermediate organism?
A4: Despite that most of the early cases seems to arise with the Huanan Seafood market, recent studies show that the human SARS‐CoV‐2 virus is transmitted by human-to-human. Indeed, the firstly documented patient had no link with this Seafood market. However, the Huanan marketplace has definitively played a role in the early spreading. For now, research shows that SARS‐CoV‐2 did not come directly from pangolins nor bats and indicate a rapid human‐to‐human transmission of SARS‐CoV‐2, whithout the. need of a intermediate organism. https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25731 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098030/
Q5: Why do so many viruses that cause epidemics originate in bats?
A5: Bats are known for hosting a wide variety of viruses, including the corona viruses. The bats seem to not be very affected by the infection by these viruses. The reason why the bats are not as sick from these viruses as us humans is suggested to be that they have evolved a different strategy for virus control. While lacking some components in the immune system, bats increase their body temperature when they fly and they have an increased metabolism. This helps them to stay healthy while the viruses can evolve in the bat population. When the virus spills over to other mammals or humans, the new host is not prepared for fighting the virus since they lack the mechanism that bats have. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012789/)
Q6: How does the SARS-CoV-2 recognize human cells?
A6: SARS-CoV-2 and SARS-CoV uses its receptor binding domain (part of a spike protein on the surface of the virus) to bind a human enzyme (ACE2), through a tightly controlled structural interface. ACE2 is an enzyme that has a role in regulation of blood pressure. It is located on the outside of the cell membrane in eg. lung epithelial cells. Binding of the virus spike protein to ACE2 on a cell facilitates the entry of the virus into the cell. SARS-CoV-2 have a few mutations in the receptor binding domain compared to SARS-CoV but they bind to and recognize human cells at the same receptor, ACE2. (https://onlinelibrary.wiley.com/doi/full/10.1002/path.1570) (https://www.nature.com/articles/s41586-020-2179-y) (https://www.ncbi.nlm.nih.gov/pubmed/20567988)
Q7: Is SARS-CoV-2 more efficent in recognizing human cells compare to SARS-CoV?
A7: The receptor-binding domain (RBD) in the spike protein is the responsible for the recognition and the binding to the ACE2 receptor and it is also the most variable part of the coronavirus genome. Curently a "binding surface" of this receptor-binding domain (RBD) have been shown to be critical for binding to human cells (to the ACE2 receptors). The composition of this surface help scientist to determine what is the host range of SARS-CoV-like viruses. The "binding surface" of SARS-CoV-2 and SARS-CoV are almost completely different. On the basis of current research on the structure of this "binding surface", SARS-CoV-2 seems to have a higher affinity with the human ACE2 compare to SARS-CoV. However computational analyses predict that the interaction between RBD and ACE2 is not ideal. However, as SARS-CoV-2 RBDs form a more stable complex with ACE2 than SARS-CoV does, result suggest that SARS-CoV-2 is indeed more efficent in recognizing human cells compare to SARS-CoV.(https://www.nature.com/articles/s41591-020-0820-9)(https://www.biorxiv.org/content/10.1101/2020.03.30.015891v2.abstract)
Q8: How many protein are encoded in virus genome and what do they do?
A8: The RNA genome of SARS-CoV-2 has 29,811 nucleotides and encodes 29 proteins (though one may not get expressed). These proteins carry out a range of jobs from making copies of the coronavirus to suppressing the body’s immune responses. Of the 29 SARS-CoV-2 proteins, four make up the virus’s actual structure, including the S protein. One group of the other 25 coronavirus proteins regulates how the virus assembles copies of itself and how it sneaks past the host immune system. These so-called nonstructural proteins are expressed as two huge polyproteins that are then cleaved into 16 smaller proteins. An enzyme called the main protease, which performs 11 of those cleavages, is also a highly promising drug target. https://www.nature.com/articles/s41586-020-2008-3, https://www.nytimes.com/interactive/2020/04/03/science/coronavirus-genome-bad-news-wrapped-in-protein.html, https://www.biorxiv.org/content/10.1101/2020.03.12.988865v2.full.pdf
Q9: What are potential antiviral therapies?
A9: Tremendous effort is currently made to rapidly find a cure for COVID-19. For now, the main research is around drug repurposing, which is taking already existing drug and test if it’s efficient against SARS-CoV-2 virus. This method can shorten the time in comparison with trying to find a novel molecule against this virus. From the preliminary data, several molecules show some effect in infected cells, (e.g. Ivermectin, remdesivir, lopinavir, sirolimus, dactinomycin, mercaptopurine, melatonin, toremifene, emodin homorringtonine, and emetine). One of the persued paths to a cure would be drug combinations which would help to hit the virus in different ways and would reduce the quantity of drug needed to be effective (so less side effect). However, SARS-CoV-2 mutate quickly which make it susceptible to escape antiviral drugs. Some researchers propose the usage of CRISPR/Cas13d system as a treatment thanks to its flexibility to adapt to its target. CRISPR/Cas13d is an RNA-targeting system, that can cleave SARS-CoV-2 RNA genome. The adeno-associated virus, a safe virus, will serve as a vehicle to deliver the Cas13d effector to infected patients’ cells. https://www.sciencedirect.com/science/article/pii/S0166354220302011 https://www.nature.com/articles/s41422-020-0290-0 https://www.nature.com/articles/s41421-020-0153-3?fbclid=IwAR2T1bk4j9DN_EjK9zGH_oABKFDRl97SePGGsatZnORg8DWB1ab7O6JXto0 https://www.sciencedirect.com/science/article/pii/S016635422030200X
Q10: Why do we observe outbreak of coronaviruses in XXI century?
A10: In our modern societies, it could seem counterintuitive that we are still sensible to pandemic outbreak. However, despite the tremendous progress in medicine and in control measures numerous diseases are emerging and spreading with an increased efficiency. Nowadays, outbreaks are more and more frequent and seems to emerge from hot spot of biodiversity at risk. Numerous studies show that, despite biodiversity being a source of pathogens, it is its decrease that cause a dramatic increase in such epidemics. Outbreak are then becoming pandemic thanks to widespread trade and increased contact between populations. (https://www.ncbi.nlm.nih.gov/pubmed/20567988) (https://www.visualcapitalist.com/history-of-pandemics-deadliest/) (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090032) (https://www.nature.com/articles/s41559-019-1060-6)
Q11: Can we prevent the rise of future outbreak?
A11: As many studies suggest that a rich and diverse wildlife limit disease spread independent of host density and type and specialization of infectious disease. It seems then that biodiversity conservation, by protecting natural areas from human incursion, is an excellent way to reduce spillover of disease from wild life to humans and will prevent future outbreak. https://www.pnas.org/content/112/28/8667 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666729/ https://www.nature.com/articles/s41559-019-1060-6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995683/
Q12: How can protein design be used to combat coronvirus infections?
A12: There are two areas where protein design is used to combat COVID-19. In vaccine design one approach is to use parts of virus to trigger the immune system to create antibodies towards the virus. Many vaccines use proteins on the surface of the virus to trigger the immune system. While it is possible to inject the surface proteins directly as vaccines, it is often better to put the surface proteins on a carrier. These carriers are often proteins that are able to form spherical particles where you can attach many copies of the protein you want the immune system to recognize. By displaying many copies you can get a stronger immune response. The spherical proteins can be designed to have optimal properties like size and number of attachment points. See for example,
https://pubmed.ncbi.nlm.nih.gov/32748788/
Vaccines are made to stop you getting infected to begin with. But what about treatments for patients already infected with COVID-19. One approach is to stop the virus from entering the cell. There are several proteins on the surface of COVID-19 that are important. However, one of the most central ones i Ace2. It is mutations in Ace2 that probably resulted in the coronavirus spreading to humans. By binding proteins to Ace2 on the surface of the virus it would not be able to enter human cells. Protein design can be used to design proteins that bind tighly to the virus and that could be injected into the bloodstream and hunt down the free virus particles to bind to them. Researchers in the Baker laboratory at University of Washington have done this and shown that it could stop the virus in animal trials.
https://pubmed.ncbi.nlm.nih.gov/32907861/
In the Andre research group at Lund University we design new spherical proteins that can be used in vaccine design. We also participate in a project to create better versions of FLU vaccines. See, andrelab.biochemistry.lu.se for updates on these results.