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COVID-19 - Coggle Diagram
COVID-19
Epidemiology
Age
- NOT DISTRIBUTED EQUALLYYYY
- More cases with middle-aged
- More deaths with elders
- Barely any child/infant cases
- Rates vary in countries bc demographics
Symptoms
- 80% mild/asymptomatic
- 15% moderate/severe
- 5% severe/death
Underlying Conditions
- CVD
- Diabetes
- Chronic Respiratory Disease
- Hypertension
- Cancer
Virology
SARS-CoV-2
Infection
Respiratory
- Direct contact
- Fomites
- Droplets (coughing)
- Airborne, if generated (aspirated)
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Incubation
Contagious period
- Peaks during second week of illness (seemingly)
Symptoms
- High fever (>38)
- Headache
- Discomfort, body aches
- Dry, unproductive cough
- Pneumonia
Entry
- Attach to host cell through ACE2 receptor
- Enters via receptor-mediated endocytosis (bc enveloped)(and takes the receptor with it)
- Releases genome
- Genome is translated (skips transcription bc it looks like mRNA)
- Produce proteins that replicate virus genome
- Transcription, translation
- Produce proteins for viral replication, immune/host modulation, virion structure
- New virion assembled
- Exocytosis
Immune Response
Severe Disease
- Could be caused by delayed innate IFN response
- High levels of viral replication —> ACE2 receptor expression increases
- Cytokine storm
- Encephalitis in areas of brain close to olfactory bulb/nasal cavity
- Ground glass pneumonia
- Intense immune activation (esp macrophage, dendritic, neutrophil- cells with Fc receptors that can take up RNA)
- Virus gene expression in host cells suspected to influence immune activation
Widespread Pathogenesis
Mild Infection
- Coordinated response, or just dampened response
- Abs against spike proteins
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Biology
Envelope
- Contains proteins needed for attachment + entry
- Susceptible to detergents + alcohols
- WASH UR HANDS (60% alcohol)
Surfaces
- Up to 72 hrs on non-porous
- Less than 4 hrs on copper
- Less than 24 hours on porous
Genome is large; there’s a nested set of discontinuous sub-genomic RNA used for protein/virus assembling
Beta-coronavirus
(most human-affecting ones are α and beta)
- Some bat viruses in this group as well
ACE2
- Angiotensin Converting Enzyme 2 (normally in renin-angiotensin pathway)
- Compatible with spike proteins
- Directs pathogenesis
- When reduced (when virus enters cell), AngII is not converted. Binds with a different receptor and promotes vasoconstriction + hypertension + lung injury + adverse myocardial remodelling
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TMPRSS2
- Involved with second cleavage event, involving furin
- Allows for fusion with membrane and release of genome into cell
Spike Protein
- Essential for virus entry
- Activated by cleaving, done by host cell proteases
- 2 methods: RBD, membrane fusion
- Each cleave is done by separate proteases
Cleavage Event 1: Attachment
- Allows S1 (RBD) to bind to new host cell
- Btwn S1 and S2
- During viral synthesis/exit, before receptor binding
- By Cathepsin L / TMPRSS2 / other proteases, in CoV-1 (and probs in CoV-2 as well)
Cleavage Event 2: Fusion
- Activates S2 domain, allows fusion with host membrane
- During viral entry, after binding
- Externally by TMPRSS2 (plasma membrane direct entry). Lets S protein mediate fusion
- Internally by Cathepsin L (endocytosis). Lets S2 mediate fusion
- Protein use here is unconfirmed, maybe a serine peptidase as well
Treatment/Recovery
Patients who recover tend to have Abs against spike protein
But older patients (more prone to severe) have highest levels of Abs
Protective efficacy not making sense
Neutralising Abs in deceased were slightly higher than that in recovered, doesn’t seem to be that beneficial
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Perhaps the Abs are actually able to continue carry the virus through Fc receptor interactions
Was shown in SARS
- Must be safe in humans
- Must work against COVID-19
- Must be easy to manufacture
- Must be deliverable in low-resource settings
Prevention
Vaccine
Must be
- Highly efficacious
- (Very) safe in humans
- Active against COVID-19
- Easy to manufacture
- Deliverable in low-resource areas
Spike Protein Disarming
- Many different candidates with different mechanisms
- Need to find really specific Abs bc the affinity is very high to the target receptor
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Receptor Binding Inhibition: RBD ACE2 Blockers
- Produce soluble ACE2 receptors that bind to RBD on Spike Protein
- Sequeter the virus before it binds to the transmembrane ACE2s
- Allows transmembrane ACE2s to function as normal
- Could potentially reduce comorbidities w/ hypertension/diabetes/CVD (related to ACE2's normal job)
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Chloroquine, Hydroxychloroquine
- Can reduce glycosylation of ACE2, affecting its function
- Might block pro-inflamm cytokine production --> dampen cytokine storm
- Can accumululate in lysosomes --> increase pH --> interfere with virus entry (wants lower pH)
- Clinical trials unsuccessful so far, unlikely to improve
Infection Control
Prevention/minimisation of cross-infections (via direct contact, aerosol, instrument/equipment)
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Inactivate vs Remove
Dependent on
- Temperature
- Moisture
- Viral structure (envelope)
- Surface survival
- Initial viral load
- Type of surface (porous)
- Susceptibility to disinfection
Public Health Campaigns
Informed by
- Disease
- Economics
- Psychology
- Compliance
- Culture
- Enforcability
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