Coronaviruses Flashcards
How many human coronaviruses have been identified?
- 7
- mostly associated with the common cold
- not well studied before SAR-CoV-2
- can be alpha, beta, delta or gamma
What kind of virus is coronavirus?
- ssRNA positive sense
- nidovirales
What are the 4 main genes in a coronavirus genome?
- structural (S)
- N protein
- M protein
- E protein
- many accessory proteins
What are some of the roles of the structural protein in the coronavirus genome?
- form large spikes on the virion surface
- bind specific cellular receptors
- induces fusion of the viral envelope with the cell membrane
- induces neutralising Abs and cell mediated immunity
What is the role of the N protein of coronavirus?
- binds viral RNA and aids in its synthesis
- forms the nucleocapsid
- also involved in cell-mediated immunity
What is the role of the M protein in the coronavirus genome?
- determines budding site
- triggers viral assembly
- forms the shell of the internal viral core
What is the role of the E protein of coronavirus?
- triggers particle assembly
- associates with the viral envelope to form an ion channel
- may cause host cell apoptosis
What are the roles of accessory proteins encoded on the coronavirus genome?
- avoiding host immune responses
- deleting these doesnt affect replication in culture but may in animals
How does coronavirus enter the cell?
- receptor binding and endosome entry
- or fusion with the cell membrane
- proteases cleave the spike proteins from the surface as/before the cell enters
How can coronavirus shield itself from the host immune response while building up metabolites/components needed for replication?
- some viral proteins induce double membrane vesicles derived from the ER
- contain intermediates of RNA replication and have a pore through which the viral genome can interact while staying protected
How does a frameshift came into coronavirus replication?
- not just 1 long ORF like many viruses
- translation of ORF1 occurs
- ribosome reaches a complex RNA structure that 5% of the time causes it to slip back 1 nucleotide, miss the stop codon and translate the rest
- acts as a way to regulate proteins needed in lower quantities such as viral replication proteins
What cleaves the polyproteins produced in coronavirus replication?
- viral encoded proteases
- NSP5 cleaves ORF1
- PLpro also involved
What proteins are encoded in the coronavirus genome? nae 6
- RNA dependent polymerase
- helicase
- RNA capping enzymes
- endo+exo nucleases
- NSP3+4 induce double membrane vesicles
- NSP1 shuts down host translation
Describe the role of subgenomic RNAs in the coronavirus genome
- produce the accessory proteins
- made as a result of discontinuous transcription
How does discontinuous transcription lead to the production of subgenomic RNAs?
- replication-translation complex reaches specific TRS elements on the genome
- RTC jumps to the 5’ end and produces sgRNA -> sgmRNA -> accessory proteins
What is the role of continuous transcription?
- to produce full-length negative sense RNA internediates that act as a template for genome replication
What is the genome size of a coronavirus compared to other positive sense RNA viruses?
- much larger
- has proof-reading enzymes while others dont
- lower accuracy of others may impose an upper limit on the size of their genomes
What are the main ORFs seen in coronaviruses?
- ORF1a = genome expression
- ORF1b = genome replication
- 3’ ORFs = virus dissemination
How does coronavirus evade the innate immune response? (5)
- encode many proteins to:
- inhibit interferon signalling or production (NSP1 can stop their translation)
- inhibiting antiviral proteins like PKR
- structural proteins like N can interfere with host defense machinery
- inhibition of inflammasomes
- inhibition of NK cells
What are 3 of the most commonly known and well studied coronaviruses?
- SARS-CoV
- MERS-CoV
- SARS-CoV2
Describe same clinical difference and similarities between SARS-CoV, MERS-CoV and SARS-CoV2
How are MERS-CoV and SARS-CoV-2 spread?
- droplets
- aerosol spread
- contaminated surfaces
Where does SARS-CoV-2 replicate + what is immunity like>
- throughout the respiratory tract
- unknown duration of immunity
Where do SARS-CoV and MERS-CoV replicate + what is immunity like>
- in the lower respiratory tract
- long-lived memory T cell response proportional to disease
What happens once SARS-CoV-2 enters the lungs?
- destruction of cells leads to inflammatory response
- in some, excessive infiltration of monocytes, macrophages and T cells leads to widespread inflammation, organ damage and cytokine storm
- in a healthy immune response the virus is cleared here or doesn’t even make it to the lungs
Where did human SARS-CoV + MERS-CoV come from?
- camels -> bats
- bats -> civets and other traded animals
- civets or camels -> humans
- mixture of cross-species and zoonotic transmission
Where did human SARS-CoV-2 come from?
- bats -> unsure intermediate host (bats?) -> humans
- mixture of cross-species and zoonotic transmission
What is the vaccine situation for coronavirus?
- 12 used worlwide and many in development for SARS-CoV- 2
- 3 candidates for MERS targeting the S protein
How did civet-infecting SARS-CoV move to infect humans?
- spike protein binds ACE-2 with a receptor binding motif
- civet and humans have similar ACE-2
- motif only needs a 2 amino acid shift to have high affinity to both ACE-2s
What kinds of issues have hampered coronavirus vaccine development in the past?
- some trials enhanced disease
- used to have a lack of understanding of the immune response to SARS
- animals cant fully recapitulate human disease
How has SARS-CoV-2 adapted to increase infection rate?
- acquired an extra furin cleavage site in the spike protein
- spike gets cleaved before leaving the host cell priming it for entry to the next one
- this mutation destabilises the virus but further mutations fixed this
- also allows binding to a wider variety of respiratory tract cells
What do we know about immunity to coronavirus?
- little
- immunity wanes rapidly
- poor understanding of how prior infection with other coronaviruses affects later infections
What is antigenic cartography>
- mapping relationships between antigenic variants of a virus
- provides a quantitative + visual summary of antigenic differences
- can see evolution of the virus and how existing treatments might fare against now/other strains
What antivirals are available for coronavirus?
- repurposed drugs
- mostly inaffective at reducing mortality, need for assisted ventilation or duration of hostpital stays
