Coronaviruses Flashcards
Pandemics
Pandemics:
- Usually caused by pathogens that haven’t been seen by the human population before (consequently, there’s no pre-existing immunity and everyone on the planet is susceptible)
- Introduction of the pathogen to humans usually comes from zoonotic source (animal)
- Happen suddenly without warning
- Pathogen transmits easily from person to person (rapid spread); Pandemics can now spread a lot more quicker than in the past due to humans travelling a lot more than before
Waves of infection, aided by increasing virulence
Zoonotic spillover event
- Pandemics have come about because we get introduction of new viruses from reservoirs into human populations
- Bat or mouse virus gets into human population through contact with a person - when an animal virus is introduced into a human population this event is called spillover
- When the virus is initially introduced during the spillover event it hasn’t adapted yet to transmit effectively but while it’s in the first person, it might pick up some changes that then facilitate transmission for it to survive in the human population
- Chance of spillover events increases as human populations come more into contact with animals through agriculture or encroaching on habitats
- Repeated spill over events can help the virus evolve to a point where it can get a hold in the human populations and transmit easily
- There’s usually spillover into intermediate hosts (typically mammal species - pigs, cows) and domestic animals ; intermediate hosts could also allow virus to pick up the necessary adaptations to transmit easily in human population
Spillover into vectors is also possible such as ticks
What is a coronavirus
- Enveloped +ssRNA viruses
- Quite large genome - 30kB in size
- Spike proteins on the surface are the attachment receptors (used to attach to human cells)
- Divided into alpha and beta coronaviruses based on their genetic makeup
- There are 4 seasonal human coronaviruses (2 alpha and 2 beta) that usually cause flu-like symptoms
However, within the beta coronaviruses, there are another couple of viruses (SARS, MERS, SARS-COV2) that infect humans and cause a lot more damage than the seasonal coronaviruses
Coronavirus lifecycle
Life cycle of coronaviruses:
- Attach to human cell and there’s internalisation receptor
- Virus uncoats and dumps viral genome into the cytoplasm
- Viral proteins are translated and genome is replicated
Together with the viral protein synthesis and viral genome replication, there’s an assembly of virions which then released from the infected cell
The first coronavirus pandemic
- The first coronavirus to cause respiratory problems was SARS
- First cases reported in China and Hong Kong
- Since patients were presenting with flu-like symptoms, it was initially believed to be influenza but was serologically different from the circulating influenza strains
- Through genome sequencing it was later determined to be a coronavirus
- First patient had stayed in a hotel in Hong Kong had gone to the wet markets where animals were sold for food - this person then infected another person in the hotel elevator who then jumped on a plane and then went to Toronto and infected many people; this is a super spreading event (1 person infects multiple people, causing a chain reaction of transmission)
- There was a cluster at the Hong Kong hotel and a cluster in Toronto and someone at the hospital there had spread it too
- If you were infected with this, you had a 50-50 chance of ending up in hospital and in ICU
- There were very limited cases but high fatality rates (10%)
- Limited number of cases was because the virus actually only transmitted and was contagious once people were really sick and presented with symptoms (unlike asymptomatic transmission)
- The world dodged a bullet because the transmission wasn’t as effective
MERS
- Second coronavirus outbreak
- Some people thought it was SARS due to the similarity in symptoms, but through sequencing it was found to be a type of coronavirus called MERS (distinct from SARS)
- Majority of the cases were in the middle east (was also thought to have emerged from the middle east) - concentrated in Saudi Arabia
- Much fewer case numbers but much higher case fatality rate than SARS (40%)
Saving grace once again was because it was a self-limiting virus (people only transmitted when they were quite sick
The role of intermediary hosts in SARS and MERS
- For both SARS and MERS, intermediate hosts were identified
- For SARS, it was a type of cat that was sold in the wet markets in Hong Kong (we got transmission of virus from bats into these cats, who then transmitted it to humans via animal-human contact at wet market)
For MERS, it was camels (important part of middle eastern culture) - believe that camels were exported from China, and these camels were animal carriers of virus
- For SARS, it was a type of cat that was sold in the wet markets in Hong Kong (we got transmission of virus from bats into these cats, who then transmitted it to humans via animal-human contact at wet market)
Sars Cov2
SARS Cov2:
- Reports started coming in from China at end of 2019
- People were presenting with acute severe respiratory syndrome, very much like SARS
- Initial tracing found that the outbreak in Wuhan linked back to the wet markets (seafood market) in China
- Around 3 months later, there were around 3000 cases, but it was largely confined to China ; at this stage WHO called this novel coronavirus a public health emergency of international concern (precursor to calling a pandemic)
- This called upon governments to enact their pandemic plans
- However, this was occurring at time of CNY - huge influx of people migrating out of China (lots of international travel)
- In the next month, the virus started appearing in other countries (particular in South east Asia) so WHO raised risk assessment from high to very high in terms of the likelihood of a pandemic happening
A couple weeks later, pandemic was declared by WHO
Where does COV2 come from?
- Animal reservoir for virus: bats from China
- Bats in general are a reservoir for lots of different viruses
- Some surveys done found that the precursor to SARS Cov2 was circulating in Chinese horseshoe bat
- Variation in the spike protein gene of the coronavirus found in the bats enabled transmission of the virus in human population
Surveys done in another region of China looked at coronavirus circulation in a small mammal called the pangolin - the coronavirus found in these pangolins was also related to SARS Cov2
How does Sars Cov-2 infect cells?
- Recognition of the virus is through the spike protein, which has adaptations that give it a high specificity and affinity for a protein called ACE2 on surface of human endothelial cells in the circulation (especially in the lungs)
- Binding of spike protein to ACE2 facilitates entry of the virus into the cells
- The spike protein has different conformations
○ Closed conformation (present in normal virion, metastable conformation)
○ Open conformation: (change in conformation after attachment and internalization)- The conformational change from closed to open requires a cleavage event by proteases, which allows the protein to unfold, which is an important step in the fusion of the viral membrane upon attachment to host membrane that allows entry and release of viral genome into the cell
- This cleavage is mediated by the expression of a protease called furin, which cleave a particular set of amino acids (arginines) which form a cleavage peptide
- Upon attachment to cell, furin cleaves the cleavage peptide which enables the conformational change of the spike protein (open conformation) which enables uncoating of the viral genome and initiation of replication cycle
Unique features of Sars COV -2
- It has acquired mutations in the spike protein gene within the receptor binding domain which provide the high specificity for ACE2 .
- The coronavirus isolated from pangolins also have this adaptation in the receptor-binding domain, meaning it can bind to mammalian ACE2 (this doesn’t tell us that pangolins are the source of the virus, but it tells us that if the virus is circulating in a particular host, it can acquire adaptations that enable it to bind to a human cell receptor)
- One of the differences between the SARS Cov2 virus and its predecessor viruses is that there is the insertion of basic amino acids (arginines) into the cleavage peptide, and this addition means that this is now a target for furin - this is not found in the predecessor viruses ; it’s not clear where this adaptation came from yet (the intermediate host is yet to be found)
What this tells us is there are different steps in adaptation - initial adaptation for ACE2 binding - acquired from infection in mammalian species, and secondly - the insertion of basic amino acids into the cleavage site was a further adaptation that enabled efficient human-human transmission. This is not found in Sars-Cov, which means the virus can’t bind ACE2 as well.
COVID SYMPTOMS
Flu: fever, aches, fatigue, headaches
SARS Cov2: shortness of breath, loss of taste and smell (sensory deprivation)
- This is a respiratory virus spread through droplets (was initially thought only to be transmitted by droplets falling onto surfaces and people touching/inhaling them but it’s now also believed to be transmitted through aerosols)
- Limiting spread involves wearing masks, good hygiene practices, social distancing etc.
Covid only affects old people. True?
- True in the sense that the older you are, the more severe the symptoms tend to be and the higher chance you’ll be admitted into hospital
But studies have found that it can affect people of all ages
What makes Sars-COV 2 dangerous
- Idea that the entire population as a whole is entirely susceptible is not quite true - studies have found some preexisting immunity (perhaps from exposure to seasonal coronaviruses) and these people either didn’t experience symptoms or had very mild symptoms when infected with SARS Cov2
The virus induces a robust inflammatory response which is part of the problem (too extreme and sustained over the course of the infection - dysregulation of immunity leads to tissue damage; cytokine storm). This has an important role in the pathology of Covid 19, and was present in individuals who required hospital admission and needed critical care
Cytokine storm
- When soluble mediators that direct and signal immune functions to ensure it’s an appropriate response get out of hand and are dysregulated
- Cytokines serve to trigger inflammation
- Normal response: inflammation subsides once infection is controlled
- Overactive response (cytokine storm): huge inflammatory response, which causes pathological tissue damage
- Release of pro-inflammatory cytokines results in mobilization of pro-inflammatory immune cells (NK cells, macrophages, T Cells), which then produce effectors that perturb normal tissue homeostasis, leading to disruption of capillary-endothelial barrier, resulting in leakage of fluid, depleted blood cells, etc - causing organ failure
Affects various tissues and organs - e.g. vasculature, heart, kidney, liver, lungs - leads to organ failure (lung failure in Covid 19, which is why ventilators are required)
