Lecture 31: SARS COV-2 Flashcards
What type of viruses are the coronaviridae family?
They are enveloped, single stranded (+) RNA viruses with spike proteins.
What types of organisms are primarily infected by coronaviridae?
Amphibians, birds, and mammals.
Why is coronavirus named as such?
Because in electron micrographs, the spike glycoprotein gives the virus a shape reminiscent of the solar corona
What is the main symptom of coronaviridae?
Mild upper respiratory illness. They are responsible for 10-30% of common cold cases.
Name the 3 major pathogenic coronaviruses that have emerged in the past 20 years.
- SARS-CoV
- MERS-CoV
- SARS-CoV-2
Describe the typical response of the body to SARS-CoV-2.
Symptoms begin one to fourteen days after exposure to the virus. Most have mild symptoms, but some people develop acute respiratory distress syndrome (ARDS).
What is acute respiratory distress syndrome (ARDS)? Include the 4 main symptoms.
It is when the immune system responds strongly to SARS-CoV-2 with cytokine storms, multi-organ failure, septic shock, and blood clots. This causes people to get very sick.
Should SARS-CoV-2 be treated with immunomodulators or anti-virals? Explain why.
Immunomodulators, as much of the severe sickness comes from the immune response rather than the virus itself.
What type of coronaviruses is SARS-CoV-2 most closely related to?
Bat coronaviruses.
What are the 4 main steps in the transmission of SARS-CoV-2 to humans from their original host?
Natural host, bats -> possible intermediate host unknown -> zoonotic transmission to humans -> human to human transmission.
What are the major and minor modes of SARS-CoV-2 human to human transmission?
Major: aerosols and droplets
Minor: indirect contact (e.g. on surfaces) - possible but not likely
What is the Baltimore classification of SARS-CoV-2?
Class 4 - (+) ssRNA virus
How many proteins are encoded by SARS-CoV-2? How big is its genome?
26 proteins. Its genome is quite large (30 Kb)
What is the shape of the capsid in SARS-CoV-2?
Helical
How many types of glycoproteins are present in the envelope of SARS-CoV-2? Name them. Which is most important?
- Spike glycoproteins (S) - most important, required for entry of virion particle
- Membrane protein (M) - most abundant viral protein
- Envelope glycoprotein (E) - smallest protein
What are the two modes of gene expression used by coronaviruses? Which is more unexpected?
Synthesis of large polyproteins that get subdivided and discontinuous transcription. While the synthesis of large polyproteins is quite standard for RNA viruses, discontinuous transcription is much more unusual.
Explain how the synthesis of large polyproteins works in coronaviruses.
They encode for a large polyprotein with one mRNA and a protease which cleaves it into smaller fragments (nonstructural proteins, nsps), each with their own function.
Explain how discontinuous transcription works in coronaviruses.
It encodes for accessory proteins individually, making different mRNAs for different proteins.
Give an example of an nsps in coronaviruses.
nsp12, which is the RdRP.
How do coronaviruses bind to the target cell? Include specific names.
Their spike protein must bind to the host receptor, ACE2.
Where is ACE2 found? What is its function?
It is found in the membranes of the lungs, arteries, heart, kidney, and intestines. Its function is to lower blood pressure.
What is the main target of vaccines against coronaviruses?
The prevention of the interaction of SPIKE with ACE2.
Aside from binding with ACE2, what is the other mode of entry for coronaviruses? State the name of the proteins involved.
Membrane fusion. The viral envelope can fuse with the cell membrane to liberate the contents into the cytoplasm. This requires that SPIKE be cleaved in 2 locations by the protein TMPRRSS2.
Give 2 examples of proteins that can cleave SPIKE upon entry by membrane fusion aside from TMPRSS2.
Furin and cathepsin B/L.
What is behind the debate as to whether coronavirus was engineered in a lab?
It has a furin binding site, which makes the virus more efficient at entering the cell. Other closely related viruses do not have one.
What is particular about the structure of the coronavirus RdRP? How does this affect the structure and behaviour of SARS-CoV-2?
It has an exonuclease, which confers proof reading activity to the replisome formed by the RdRP that replicates the genome. This prevents the typical rapid mutation that comes from error catastrophe in viruses and allows it to have a large genome, as minimal mistakes are made.
Why is the rapidly evolving nature of SARS-CoV-2 unexpected?
Because it has the proof-reading exonuclease in the RdRP, which would normally reduce the rate of mutation. But in reality, it can evolve very rapidly.
What are the two typical morphological changes observed in cells infected with CoV?
They will have either double-membrane vesicles (DMVs) or convoluted membranes (CMs).
Why do coronaviruses create DMVs and/or CMs in their host cells?
This makes it easier for the viruses to self-replicate in the small compartments that result from the modified structure, thus condensing all the viral replication organelles into one small space.
Give an example of a major drug target in the CoV life cycle.
The RdRP, as inhibiting this would essentially kill the virus, as it wouldn’t be able to replicate.
Describe how antiviral drugs utilize RdRP as a target.
Drugs that look like ribonucleotides can be mistakenly used by the RdRP, which will prevent a functional chain from being transcribed/translated by the RdRP.
Give 2 examples of ribonucleotide analogue antiviral drugs.
Remdesivir and molnupiravir
How does Remdesivir work and when should it be used?
It works by blocking the RdRP in the act of transcription/translation. It must be used very early - by the time patients are hospitalized it is too late.
How does molnupiravir work?
It gets incorporated by the RdRP into the viral RNA. It creates an abundance of mutations, leading to non-functional genomes and error catastrophe.
Give an example of a protease inhibitor drug against coronavirus.
Paxlovid.
How does paxlovid work?
It inhibits the 3CL protease, which is needed to cleave the polyprotein in the coronavirus. This will force the polyprotein to remain whole, preventing the individual proteins from being active.
Paxlovid is normally given with what other drug? What is the purpose?
Ritonavir. Its function is to slow the metabolism of paxlovid to keep concentrations higher.
What is the main vaccine technology used against SARS-CoV-2?
mRNA vaccines
What is variolation?
It was an ancient form of immunization where people were innoculated from Variola virus using pus from Cowpox virus, which is similar but less virulent.
Name the best-studied poxvirus.
Vaccinia virus.
Describe what mRNA vaccines are and how they work.
They consists of mRNA encoding the antigen of choice (e.g. SPIKE for covid) encapsulated in lipid nanoparticles. After injection, protein production in muscle cells peaks for 24-48 hours.
Name an advantage of mRNA vaccines.
They are simple and quick to synthesize, scale up, and purify.
Name a disadvantage of mRNA vaccines.
They are very easy to degrade and an be destroyed by the immune system.
What are the 2 ways in which the mRNA vaccine for covid overcomes the disadvantages of mRNA vaccines?
It overcomes the issue of instability and easy degradation by:
1. Chemical modification of building blocks (use of pseudouridine)
2. Packaging the proteins into lipid nanoparticles
What is a variant of concern (VOC)?
It is a variant for which there is evidence of an increase in transmissibility, more severe disease, reduction in neutralization by antibodies generated during previous infection, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.
What is the most prevalent VOC for SARS-CoV-2?
Omicron.
How does the structure of Omicron compare to the structure of regular covid? How does this affect its functioning?
It has more than 50 mutations, including 30 affecting the spike protein. This makes it less susceptible to vaccine-induced immunity, but it is also milder in terms of symptoms.
Name 3 consequences of animals getting infected by SARS-CoV-2.
- Endemicity
- Mutation pressure (variant evolution)
- Secondary spillover to humans
What animal has been identified as a source of new covid variants for human?
White-tailed deer.
