Immunity to COVID-19 Flashcards
1
Q
4 common coronavirus
A
- OC43
- HKU1
- NL63
- 229E
2
Q
Covid-19 Virus Structure
A
- single strand RNA virus
- 30’000 NTs
- Spike glycoprotein - gets virus into cell
3
Q
Where are most changes in COVID variants seen?
A
- RBD domain of the spike protein
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
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
6
Q
SARS-CoV-2 origins
A
- Rhinolophidae insectivorous bat family associated with SARS-like CoV
- Closest relative is RaTG13 (96% homology)
7
Q
COVID-19 Risk Factors
A
- Age (over 65 yrs)
- Male
- Diabetes
- Hypertension
- Obesity
- COPD
- Chronic Kidney Disease
8
Q
What protein and what receptor are involved in COVID-19?
A
- spike protein binds to ACE-2 receptor
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)
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
- Cytokines (IL-1β, IL-6, TNF𝛼, IL-8, IL-18)
- IFNs ( IFN𝛼, IFNβ, type III IFN)
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
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
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
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
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
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
- Sinovac - virus grown in cell culture and then inactivated
- Moderna - mRNA from spike gene injected
- AstraZeneca & Janssen
- 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
