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MB3008 > Immunity to COVID-19 > Flashcards

Immunity to COVID-19 Flashcards

1
Q

4 common coronavirus

A
  • OC43
  • HKU1
  • NL63
  • 229E
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2
Q

Covid-19 Virus Structure

A
    • single strand RNA virus
  • 30’000 NTs
  • Spike glycoprotein - gets virus into cell
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3
Q

Where are most changes in COVID variants seen?

A
  • RBD domain of the spike protein
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4
Q

Omicron Variant

A
  • Replicates 70x faster in bronchi and less efficient at replicating in lung epithelia
  • Associated with URT while delta associated with LRT
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5
Q

How do variants emerge?

A
  • more people infected - greater chance that mutations will arise giving the virus an evolutionary advantage - darwinian evolution
  • natural selection for mutants - allow virus to propagate more efficiently
  • multiple mutations can arise - persistent infection of immunocompromised patient - escape mutations
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6
Q

SARS-CoV-2 origins

A
  • Rhinolophidae insectivorous bat family associated with SARS-like CoV
  • Closest relative is RaTG13 (96% homology)
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7
Q

COVID-19 Risk Factors

A
  • Age (over 65 yrs)
  • Male
  • Diabetes
  • Hypertension
  • Obesity
  • COPD
  • Chronic Kidney Disease
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8
Q

What protein and what receptor are involved in COVID-19?

A
  • spike protein binds to ACE-2 receptor
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9
Q

Protease(s) required for spike protein to gain access?

A

TMPRSS2 (Transmembrane protease serine-2)

  • critical for fusion of virus with host cell membrane
  • required for cell entry
  • located on epilepsy cells in lung (absent in URT)
    • Omicron does not bind well to TMPRSS2

FURIN

  • cleaves unique AA sequence (PRRA)
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10
Q

Immune response to SARS-CoV-2

A
  • innate system - quick and effective protection
  • TLR/7 & 8
    • senses virus ssRNA - mainly by pDCs
  • TLR3
    • senses dsRNA intermediates
  • RIG-1/MDA5
    • senses cytoplasmic viral RNA
  • Inflammasome
    • activated by viral proteins (ORF3a and ORF8b)

Leads to triggering of NF-KB and IRF TFs….. leads to production of

  1. Cytokines (IL-1β, IL-6, TNF𝛼, IL-8, IL-18)
  2. IFNs ( IFN𝛼, IFNβ, type III IFN)
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11
Q

Impaired IFN response associated with COVID-19

A
  • COVID proteins inhibit various parts of innate response and IFN activity
  • SARS2 has antagonistic mechanism against IFN signalling
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12
Q

Use of IFNs in COVID-19

A
  • timing is key - if given too late - disease can worsen
  • administration of recombinant IFNs (IFN-𝛼, IFN-A) - early stage
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13
Q

B cell responses to SARS-CoV-2

A
  • induces durable B cell response - ab levels decay over time (first 4 months)
  • infection triggers heterogeneous ab response
  • LLPS present in bone marrow up to 11 months
  • Severely ill patients
    • somatic mutation in VH genes in GCs - high affinity ab
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14
Q

Characteristics of Immune Response in severe COVID-19 patients

A
  • ARDS - dyspnea and hypoxemia
  • cytokine storm - increase in IL-6, Il-8, TNF-𝛼, IP10 - comes from lungs where there is high abundance of inflamm macrophages
  • sluggish NFs and monocytes
  • NFs are immature
  • reduced and exhausted DCs
  • Low IFN production
  • T cell lymphopenia - lymphocyte death by apoptosis
  • Exhausted NK cells
  • excessive amounts of proinflamm molecules - promote vascular permeability and organ damage
    • hypercoagulation
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15
Q

Lab tests indicative of severe infection

A
  • Increased IL-6, IL-8, TNF-𝛼, IP10 in serum
  • Elevated C-reactive protein (C-RP) - produces in liver in response to infection
  • Elevated D-dimer - fibrin degradation product present after blood clot
  • Elevated NFs - immature phenotype
  • Decreases lymphocytes
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16
Q

Agents capable of reducing infection severity

A
  • anti-clotting drugs
  • immune-dampening steroids
  • Dexamethasone - inhibits cytokine production
17
Q

Immunomodulatory Treatment Options

A
  • Monoclonal abs - blunt the cytokine storm - blocks effects of cytokines (IL-6, IL-8, TNF𝛼)
    • inhibitors of IL-6 (siltuximab)
    • inhibitors of IL-6R (tocilizumab)
  • Baricitinib - inhibitors of cytokine production
  • Dexamethasone - broader acting steroid
  • IFNs
18
Q

Glucocorticoids

A

Dexamethasone & Prednisolene

  • immunosuppressants
  • SE: inhibition of host immune response to pathogens
  • inhaled vs systemic
  • Blocks NF-KB by binding to p65 subunit
19
Q

Antivirals

A
  • Molnupiravir - RNA-dependant RNA polymerase inhibitor
  • Paxlovid - SARS-CoV-2 protease inhibitor
20
Q

Monoclonal abs to spike protein

A
  • passive immunisation
  • Regeneron - 2 mabs
    • casirivimab
    • imdevimab
    • bind to non overlapping epitopes of spike protein RBD
    • not effective for Omicron - too many mutation in AAs of spike
  • Bamlanivimab - 2 mabs
    • bamlanivimab
    • etestevimab
    • neutralising mAbs - bind to overlapping epitopes of spike protein RBD
21
Q

Types of vaccines

A
  1. Sinovac - virus grown in cell culture and then inactivated
  2. Moderna - mRNA from spike gene injected
  3. AstraZeneca & Janssen
  4. Novavaz - subunit rSpike protein
22
Q

Conformations of spike proteins

A
  • pre-fusion standing up conformation
  • post-fusion flat, lying down conformation

Vaccines have engineered changes to spike protein to keep it in standing up conformation

  • moderna mRNA
  • Pfizer mRNA
  • J&J
23
Q

Features of mRNA vaccine design

A
  • NT modification - substitution of Uridine for Pseurdouridine
    • protects mRNA from nuclease degradation
  • Use of preferred codons from translation in human cells
    • Lysine has 2 codons (AAG or AAA) - AAG preferred in humans
24
Q

Lipid Nano Particles

A
  • used to protect mRNA and allow its delivery through plasma membrane
  • released into cytoplasm for translation on ribosomes

Multicomponent lipid

  • ionisable lipid - complexes with mRNA to form core structure
  • phospholipid - helper lipids - envelope lipid-mRNA complex
  • cholesterol
  • PEG-lipid - protects shell of nanoparticle
25
Q

How does mRNA vaccines trigger Innate response, Ab response and T cell immunity?

A
  • RNA/LNP taken up by muscle cells and APCs
  • Sensed by TLR7/8 by RIG-1 - promotes IFN secretion
  • mRNA translated by ribosomes into polypeptides - processed by proteasome - presentation of peptides onto MHC I
  • Secreted proteins detected by abs and APCs
26
Q

Glucocorticoid Mechanism

A
  • Prednisolene and Dexamethasone
  • bind to p-65 subunit and blocks NF-KB signalling

MB3008 (9 decks)

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