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3s2: Infection and Immunity > Week 10 > Flashcards

Week 10 Flashcards

1
Q

What is a general idea of RNA viral strategy?

A

RNA viruses: low coding capacity. Rely on rapid mutation rates and multifunctional proteins for survival

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2
Q

What is a general idea of DNA viral strategy?

A

DNA viruses: high coding capacity. Rely on recombination with the host genome to grab proteins that can increase survival

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3
Q

What is an overview of viruses?

A

Very small and cannot be filtered
Obligate intracellular replication
Discovery of viruses - Tobbaco mosaic virus (1892) then Foot and Mouth Disease Virus (1898)
Virus is Latin for poison

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4
Q

What is a basic idea of RNA and DNA virus repliacation?

A

In cells ‘DNA makes RNA makes protein’.
Viruses are ‘nucleic acid in a protein box’.
DNA is made and read in the nucleus. DNA viruses will be found in the nucleus and need to make viral RNA
RNA is read in the cytoplasm. RNA viruses just need to find ribosomes

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5
Q

What are examples of DNA viruses?

A

Pox
Herpes
Adenoviruses

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6
Q

What are the different types of DNA viruses?

A

DNA viruses can be single strand (ss) or double strand (ds)
Single strand DNA viruses can be (+) (5’ to 3’) or negative (-) (3’ to 5’) strand

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7
Q

What is a simple mechanism for DNA viral replication?

A

Viral DNA is transported to the nucleus and replicated, it then codes for viral m-RNA which moves to the cytoplasm

Viral m-RNA uses ribosomes to make viral proteins which assemble with viral DNA to make new virus

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8
Q

What are retroviruses?

A

Viruses that integrate DNA into host genomes

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9
Q

What is the mechanism for retrovirus replication?

A

Viral RNA is converted to ds DNA by viral reverse transcriptase
This DNA is integrated into host chromosome in the nucleus by viral integrase
Integrated viral DNA is read like host genes to make m-RNA which is translated by ribosomes to make viral proteins

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10
Q

What is an overview of virus taxonomy?

A

Seperated into either DNA or RNA then seperated into single stranded (+ or -) or double stranded with retro viruses being closer to DNA viruses

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11
Q

What are the three main methods of viral genome organisation?

A

Linear
Circular
Segmented

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12
Q

What are the difference in transcription for single vs double stranded viruses?

A

Double stranded genomes can read off both strands to make more proteins
Single stranded only read off in a single direction

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13
Q

What is the difference between human genome size and number of proteins produced compared to some viruses?

A

Humans 3x10^9 Kb makes 20-50,000 proteins
Smallpox 130-375 Kb makes 110-200 proteins
HIV 7-12 Kb makes 10-11 proteins

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14
Q

How do viral small genomes do so much damage?

A

One m-RNA can make many different proteins and each viral protein has many functions

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15
Q

How do viruses make multiple proteins from one m-RNA?

A

VIRAL PROTEASES AND FRAME SHIFTS CAN INCREASE PROTEIN EXPRESSION FROM A SINGLE MESSAGE

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16
Q

What is an overview of frameshift increasing protein number?

A

Polyprotein processing using a viral protease generates different combinations of amino acids and therefore proteins with different functions
Frame shift results from ‘stuttering’ of viral polymerase on viral genome

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17
Q

What is an overview of dengue virus?

A

Dengue virus is an enveloped (+) single strand RNA virus that causes Dengue fever.
The envelope fuses with the endosome releasing viral RNA into the cytoplasm where it is replicated translated into viral proteins to make new virus.

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18
Q

What is conserved evolutionary feature?

A

Mechanism of fusion of virus envelope with endosomes. This is the same for many viruses
Use of viral protease to generate several viral proteins from a viral polyprotein

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19
Q

What is an overview of influenza virus?

A

Influenza virus is an enveloped (-) single strand RNA virus with a segmented genome.

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20
Q

How do negative strand RNA viruses like influenza replicate?

A

(-) strand RNA has to be made into (+) strand RNA by a viral polymerase attached to the RNA. This is illustrated as a protein complex surrounding the RNA. This complex needs host RNA polymerase so it has to go to the nucleus to start making (+) RNA

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21
Q

What is an overview of HIV?

A

HIV is a retrovirus. It is an enveloped virus containing two (+) single strand RNA genomes

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22
Q

How do retroviruses work?

A

Viral RNA is made into DNA by reverse transcriptase in the cytoplasm. The viral DNA is integrated into host DNA in the nucleus by a viral integrase

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23
Q

What is an overview of the sucess of anti-virals?

A

THERE ARE VERY FEW ANTIVIRAL
DRUGSBUT RECENT SUCCESS WITH HIV AND HEPATITIS-C!

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24
Q

What is the most common outcome for viral infections?

A

IN MOST CASES VIRUSES ARE REMOVED BY THE IMMUNE SYSTEM AND CONTROLLED BY VACCINATION

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25
Q

What are the different patterns of virus infection?

A

Acute - viral load increases after a couple days immune system kicks in and load decreaes (rhinovirus)
Progessive - viral load increases after a couple days immune system kicks in, load slightly decreases before increasing again (Dengue virus, Ebola virus, HIV)
Latent - Latent reactivating after each wave is defeated by immune system
Chronic/persistent - viral load increases after a couple days immune system kicks in but virus isnt removed present at lower levels (hepatitis C)

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26
Q

What makes makes viral infections latent?

A

They do not make proteins and are invisible to the immune system.
The immune response dies down but environmental changes can reactivate replication and infection (herpes virus: Epstein-Barr, measles).

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27
Q

What is an overview of Herpes Varicella-zoster?

A

Herpes Varicella-zoster (chicken pox) is transmitted by breathing in virus or contact with mucosal surfaces
Replicates at mucosal surfaces (10- 20 days) causing fever, transmitted to blood, and from there to epithelial cells of skin
Skin rash occurs because of immune response.

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28
Q

What is an overview of SHINGLES: VARICELLA-ZOSTER?

A

Chicken pox also infects sensory ganglia. genome does not integrate and stays in nucleus where virus genes are shut down.
Later stress signals activate genome and many virus infects epithelial cells (shingles)
SHINGLES CAN BE RESTRICTED TO DERMATOMES (AREAS OF THE TORSO) SUPPLIED BY SPECIFIC NERVES

29
Q

How do viruses cause damage?

A

Viral infections are dangerous when they generate uncontrolled inflammation
Inflammation is part of the bodies defence against infection Immune responses can damage tissue
This damage can come from the act of viral replication or by immunity and cytokines

30
Q

How many people do viruses kill?

A

1918 - H1N1 ‘Spanish Flu’ 50 million deaths
2006 - Hepatitis C identified by Chiron - 200 million infected, 70%-chronic liver disease, cancer
WW2 - 50 million

31
Q

What is an overview of immune response to infection?

A

Type 1 interferon from infected cells cause anti-viral state then fever and inflammation
Acquired immune responses to infection generate T-helper cells secrete cytokines to: amplify cytotoxic T-cells and provide help to B-cells which secreted IgA enters

32
Q

Why do you get influenza every year?

A

DURING THE YEAR THE INFLUENZA VIRUS HAS MUTATED. THE OLD T-CELLS DON’T RECOGNISE THE VIRUS. YOU NEED TO START OVER AGAIN
Though vaccines can be produced to counter the most common strains

33
Q

How do different RNA viruses reproduce?

A

RNA dependent RNA polymerase(+)
(-) strand used as a template for m-RNA(+) strand used as a template for (-) strand
Double strand intermediate m-RNA makes new viruses

34
Q

What is unusual about double-stranded m-RNA?

A

RNA VIRUSES MAKE A DOUBLE STRANDED RNA.
DOUBLE STRANDED RNA NOT NORMALLY MADE IN CELLS

35
Q

How can viral nuclic acid trigger immunity?

A

Viral nucleic acid is recognised by RNA helicase proteins in the cytosol and Toll-like receptors (TLR) in endosomes
Helicase can recognise products of RNA dependent RNA polymerase (dsRNA) eg MGA5
TLR can recognise high CG content and methylation state of viral DNA eg TLR3

36
Q

What happens after TLR and helicases detect DNA?

A

RNA helicase proteins and Toll-like receptors signal through interferon responsive transcription factors that switch on interferon genes eg IRF3 or IRF7
Pathways coupling virus recognition to INF- a and b gene expression utilize IRF transcription factors.

37
Q

What are the effects of interferons?

A

THE INTERFERON IS SECRETED AND BINDS INTERFERON RECEPTORS ON CELLS CLOSE BY.
Interferon changes expression of 300+ genes
EFFECTORS OF INTERFERON SLOW VIRUS REPLICATION, PROVIDE INNATE IMMUNITY AND ‘ANTIVIRAL STATE’

38
Q

What are the effects interferons have on other genes?

A

Promote adaptve immune response
P-elF2alpha increase apoptosis
Mx proteins block viral addembly
Fv,Trim5alpha sequester capsid proteins

39
Q

What are examples of viruses that target interferon immunity?

A

Hepertitis C inhibits TLR3 signalling
BVDV inhibits degradation of dsRNA
Rotaviruses inhibits IRF-3 (Interferon regulatory factor 3)

40
Q

What is cytokine storm?

A

Over stimulation of cytokines results in
immune-infiltration into lungs: pneumonia: loss of oxygen
Large scale immune cell infiltration into the airways from the blood causes pneumonia

41
Q

What happens during a cytokine storm?

A

Type 1 interferon triggers pro-inflammatory cytokines IL6, IL1,TNFa, MCP-1 which promotes neutrophil, macrophage, T cell, B-cell

42
Q

What are possible therapies for cytokine sotm?

A

Inhibition of INF with antibodies
Inhibition of IL1, IL6 or TNFawith antibodies
Inhibition of inflammation with dexamethasone
Reduce virus replication: anti- virals

43
Q

What is a simple guide to acquired immunity?

A

T helper cells help B- cells and Tc cells
B-cells make antibodies
T-cells kill infected cells

44
Q

What is a break down of the amount of genes that make B cells?

A

40 variable genes
25 diversity genes
5 joining genes
Constant genes
Only one of the duplicated sequences is used by the antibody

45
Q

What is an overview of gene rearrangement?

A

Gene rearrangements select variable region and hook it onto the constant region. Each B-cell can only do this once
This is VDJ recombination
Rearranged Ig genes encode mRNA to make antibody protein

46
Q

How much diversity does VDJ recombination provide antibody and T-cell diversity?

A

V gene pairs 1.9 x 10^6J diversity 3.0 x 10^7
Total diversity 5.0 x 10^13 theoretical calculation
There are about 10^11 stars in the milky way

47
Q

What is the importance of T-cells for viral immunity?

A

T-cell mediated immunity: is very important for B cell help and in anti-viral immunity
T-cell receptors are not a class of immunoglobulin, they resemble immunoglobulin but are made by different genes that rearrange but are only expressed in T-Cells

48
Q

What is an overview of the rate of antibody variation?

A

T-and B-cells rearrange genes at random (10 million each day). We are making antibodies against SARS all the time

49
Q

What happens when the right B and T cell are found?

A

Cells that have rearranged the right gene segments make an antibody that binds antigen. Antigen binding triggers cell division. This is clonal expansion
Clonal expansion generates large numbers of cells making the same receptor. The other cells die.

50
Q

What is an overview of B cell T cell communication?

A

Memory B cells retain a membrane bound immunoglobulin and can use this to communicate with T-cells
When the B-cell and T-cell agree that there is an antigen the T-cell secrets cytokines to activate the B-cell.

51
Q

What is an overview of B cell response to infection?

A

Plasma B cells remove the membrane anchor and secrete immunoglobulin
If a virus infects very rapidly there is not enough time to make the right B-cells before the virus has caused disease.
Vaccination speeds up the generation of antigen specific B-cells.

52
Q

What is an overview of memory cells?

A

MEMORY CELLS GENERATED IN PRIMARY RESPONSES PROVIDE LONG-LIVED IMMUNITY
IL10 from T-cells drives plasma cells to secrete antibody

53
Q

What is the function of vaccines?

A

Vaccines generate memory B-cells and memory T-cells
So induce quickier adaptive immune response

54
Q

What is an overview of Covid-19 replication?

A

(+) STRAND RNA VIRUS
Genome behaves like m-RNA and is read by ribosomes to make one polyprotein
Polyprotein is cut up by proteases to make functional proteins
Replicase proteins make new genome from RNA template

55
Q

What was the main target of the covid-19 vaccine?

A

Research has focussed on the spike protein which is used by the virus to enter cells by binding ACE2 receptor

56
Q

How does the spike protein target promote infeciton?

A

Spike binds ACE2
Transmembrane protease modifies spike to allow entry

57
Q

What were the two main vaccine types?

A

The sequence of the spike is used to generate c-DNA that is incorporated into two main vaccine formulations:
* adenovirus vectors
* m-RNA

58
Q

What is an overview of ADENOVIRUS VACCINE FORMULATIONS?

A

The sequence of the spike is used to generate c-DNA that is incorporated into adenovirus vectors
Astra Zeneca: chimp adenovirus ChAdOx
Johnson and Johnson: human adenovirus

59
Q

What is an overview of RNA vaccines?

A

The sequence of the spike is used to generate c-DNA that is incorporated into mRNA vectors
Make mRNA for spike ‘in vitro’
Optimise translation and stability to reduce inflammatory responses
Pfizer BioNTech
Moderna name means ‘modified RNA’

60
Q

What is the method for RNA vaccines?

A

Make RNA from a DNA template using phage RNA polymerase. Add 5’ Cap and poly A tail
Use 5’ and 3’ UTR from viruses to increase translation and stability
Use modified pseudo-uridine to increase stability and reduce inflammation

61
Q

What can be done to reduce rna vaccine side effects?

A

FPLC to remove double stranded RNA to reduce inflammation
Package into liposome vector

62
Q

How can you make RNA vaccine using phages?

A

RNA polymerase. Have 5’ Cap and poly A tail
1 and 4 make RNA from a DNA template using phage RNA polymerase. Have 5’ Cap and poly A tail
Use 5’ and 3’ UTR from viruses to increase translation and stability
Use codon optimisation and modified pseudo- uridine to increase stability and reduce inflammation

63
Q

What is the virological arms race?

A

Virus replication vs Antibody and T-cell diversity

64
Q

What is something that gived viruses an edge?

A

Virus replication is not an exact process.
Genome replication: RNA polymerases (and in the case of retroviruses, reverse transcriptase) have low proof reading capacity and make mistakes

65
Q

What is an overview of virus quasi species?

A

1 error every 10^3 - 10^5 bp
3-32 Kbp genome of RNA viruses means an average 0.1-1 mutations per template copied

66
Q

What is an overview of the virus immune system arms race?

A

Most viruses lose the arms race eg: rhinovirus, influenza, hepatitis A
Gene rearrangement in B and T lymphocytes in lymphoid organs provides the rapid response and diversity needed to counteract virus evolution

67
Q

What is an problem with escape mutants?

A

Some viruses win the arms race: ‘immune escape’ mutants allow the virus to survive eg: HIV, HepC

68
Q

What is an overview of proof reading in SARS?

A

GOOD NEWS FOR SARS/COVID19. THE POLYMERASE HAS PROOF READING. MUTATION RATES ARE RELATIVELY LOW.

69
Q
A

3s2: Infection and Immunity (12 decks)

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