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Rob's Microbiology MCD > Micro 5: Viral evasion of host immunity > Flashcards

Micro 5: Viral evasion of host immunity Flashcards

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Biology 101 flashcards
1
Q

How can the immune system detect viruses

A

Viruses are intracellular pathogens and so their proteins are easy targets for processing and presentation by MHC.

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2
Q

What parts of the virus is an immune response mounted against

A

The MHC can present all parts of the viruses, not just the outside.

The antibodies will be made obviously to surface molecules

But the inside of the virus can be preseted on MHC and this can trigger CD8+ T cell to kill the virally infected cell

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3
Q

What is more variable, internal viral proteins or surface molecles?

A

Internal viral proteins can be targets of cellular immunity. They tend to vary less than surface antigens.

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4
Q

T/F a virus can be chronic without interfering with cellular immuity

A

F…

Viruses that persist must evade cellular immunity

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5
Q

Give an example of a family of viruses that evade cellular immunity

A

. The family of herpes viruses are the classic examples.

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6
Q

Outline presenation of internal peptides inside a cell

What is TAP

A

Proteins in cell chopped up by proteosome,

peptides transported into the ER where they are loaded onto MHC class 1 and the b2-microglobulin is added

This is then transported through the golgi apparatus and displayed on the surface of the cell

The peptide being presented can then be seen by a T cell receptor on a T lymphocyte

TAP is the protein used to translocated processed peptides from the proteasome into the rER for binding to MHC

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7
Q

Which cells in th ebody expresses class 1 MHC

A

All

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8
Q

What activates the T cell

A

The MHC 1, TCR, foreign peptide and CD8 is important too

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9
Q

How do HSV 1 prevent interfere with cellular immunity

A

HSV ICP47 blocks access of the processed peptide to TAP

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10
Q

How does EBV evade cellular immunity

A

EBV EBNA1 cannot be processed by the proteasome

so the viral protein cannot be chopped up and put into the ER so it cannot be presented in MHC class 1 to activate T cell

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11
Q

What is the name of the protein that transports peptides into the ER

A

TAP

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12
Q

How does CMV evade cellular immunity

A

CMV US6 stops ATP binding to TAP preventing translocation

CMV US3 binds tapasin and prevent peptides being loaded to MHC

(i.e. cuts off the energy to TAP so peptides can’t get into the ER and thus cannot be associated with the MHC molecules and cannot be presented to the T cells)

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13
Q

Which molecule assists in loading the peptide onto the MHC

A

Tapasin

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14
Q

How can adenovirus effect cellular immnity

A

Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum

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15
Q

How does the KSHV (HHV8) evade cellular immunity

A

KSHV kK3 protein induces polyubiquitinylation and internalization of MHC.

From the internalized endosome, MHC is passed to lysosomes where it is degraded.

Cannot present viral proteins to the T cell

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16
Q

What type of virus is the HPV

A

DNA virus, but with shorter genome than herpes

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17
Q

How does HPV evade the immune response

A

Both cellular and innate response

Just note that because HPV has a small genome, its proteins often do diverse range of functions

E6/E7 are oncogenic (interfere with cell cycle), but they are also binding to proteins involved in the interferon detection pathway (cGAS, STING etc) and the IFN-a effector pathway (innate).

E7 also prevents transcription of MHC and TAP proteins

E5 holds onto the MHC class 1 molecule in the ER and the golgi and prevents it from being transported to the surface (cellular)….. BUT think about the consequence of loss of MHC

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18
Q

What is the human response to lack of MHC on cells

A

This makes immune system think there is virus in the cell

So loss of MHC1 activates NK cells

Normal healthy cells display MHC at their surface.
Cells that don’t display MHC are detected by NK cells and killed.
Viruses that disrupt MHC presentation would end up being killed by NK cells.

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19
Q

How do viruses get around the NK response which kills them if they interfere with MHC

Give an example

A

Viruses encode MHC analogues (CMV gpUL40) or upregulate MHC.

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20
Q

What are virus vaccines usually trying to achieve

A

An antibody response

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21
Q

What is antigenic drift, vs antigenic shift

A

Continued rapid evolution driven by antigenic pressure from the host= antigenic drift

Introduction of new subtypes from animal source= antigenic shift

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22
Q

Give example of antigenic drift and shift

A

Drift: influenza antigenic drift + HIV quasispecis

Shift: influenza antigenic shift

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23
Q

What is a quasi species in relation to antigenic drift

What is the difficulty for treatment

A

It’s when HIV replicates inside you it and spits out lots of different variants of the virus (=antigenic drift)

The body can’t mount reponses against each subtype of the virus and contain it because of all of the different surface molecules

24
Q

Outline the differences in the number of serotypes with viruses and the consequences for vaccination

A

There is antigenic variation existing as different genetically stable serotypes that cocirculate in humans

Rhinovirus- 100s
Polivoris- 3
Dengue- 4

Consequence is theat the polio and dengue viruses nit to be trivalent and quadrivalent respectively

The rhnovirus it is impossible to get a vaccine to promote immunity against so many serotypes… and not worth it cos only common cold anyway

25
Q

What drives influencza antigenic change

A

EVOLUTIONARY PRESSURE DRIVES ANTIGENIC CHANGE IN INFLUENZA

ABs bind to viruses and is neutralised

26
Q

What do ABs bind on influenza

A

Haemagglutinin= major influenza viral spike antigen

It has head and stalk domain. A trimer

27
Q

Outline the conservation of haemagluttinin

A

There are some AAs which are highly conserved and some which are highly variable between different haemagglutinin molecules

The head domain (which pokes out most into the external environment) is highly variable

28
Q

Why is the head domain likely to be variable in the haemagglutinin molecule

A

So that the B cells don’t mount an immune response to it (i.e. the AA are constantly changing so that previously formed ABs cannot bind them)

=ESCAPE. This is the basis of antigenic drift

29
Q

What is the head resonsible for in haemagluttinin

A

Binding to the cells influenza wants to infect (i.e. respiratory epithelium)

The target of B cells to make antibodies against it

=HA1

30
Q

How much do AAs have to change within the haemagglutinin molecule in order to prevent preformed AB binding

A

If the haemagglutinin has only a couple of AAs change, it will escape the preformed antibodues

31
Q

Which part of the haemagluttinin has conserved AAs and why

A

The stalk (=HA2)

Maybe because the protein is so critical to the virus that it cannot be varied (not selected for)

OR

no evolutionary pressure yet (only a tiny fraction of the antibodies actually see the stalk, they se the head)

32
Q

How could a universal influenza be developed

A

Develop AB to the part of the haemagglutinin which is conserved and integral to its function and thus present on every haemagglutinin thus alowing us to target every strain of influenza

33
Q

How do we know whether we need to update flu vaccine

A

You look at the variable part of the haemagglutinin molecule on Influenza A virus H3N2 (which is the virus causing seasonal flu)

To see if they have changed enough such that ABs produced from pre-administerd vaccines will not longer be specific enough to bind the haemagglutinin

You look on antigenic cartography

34
Q

Why is it so difficult to vaccinate against influenza

A

H3N2 antigenic drift is rapid and many clades co-circulate

35
Q

Outline the process of deciding which flu vaccne to make

A

Collection of influenza samples from infected people, genetics (i. sequence them) and antigenic characterisation (incl antigen cartography), WHO recommends vaccine strains

These vaccine strins are then grown in bulk

When you do antigenic cartography, if the viruses are all very close together then you don’t need to update the vaccine, but if the dots are diverging then you need to update

36
Q

What happens if the correct flu strain isn’t chosen for vaccine

A

The selected strain could be a poor match with the predominant circulating virus.

Low efficacy

37
Q

What area of haemagluttinin does ‘broadly neutralising Ab’ attack?

A

Broadly neutralising Ab (bnAb) attacking stem region

38
Q

Is the the bnAb currently used?

A

No,

Current vaccines generate specific Ab responses raised against immunodominant HA1 epitopes at five antigenic sites (Sa, Sb, Ca1, Ca2, Cb)

Basically the conserved regions of the haemagglutnin has been found but the immune system hasn’t really developed many T cells against it because it doesn’t see it enough (the head is the area exposed to the immune system)

You need to get the immune system to see the conserved area if you want to develop the universal influenza vaccine that tackles all types of the virus

39
Q

Ideas for development of universal influenza vaccine (i.e development of the bnAb antibody which targets HA2?)

A
  1. Headless HA
  2. Hyperglycosylating HA1 head domain (so that the immune system can’t see HA1 and just focuses on HA2)
  3. Peptides against fusion peptide (FP) and ectodomain (EHA2)
  4. Ferritin based nanoparticles displaying HA
  5. Sequential immunization with Chimeric HA
40
Q

How could ferritin based nanoparticles work in influenza

A

displaying HA
then allows more room for B cells to come in and
but with more space etween HA molecules and this recognise the stalk part of the antigen which is usually hidden away

41
Q

How could Sequential immunization with Chimeric HA help to develop universal influezna vaccine

A

Could keep changing HA1 and keep HA2 conserved when giving booster vaccines

This will make the immune system focus on the conserved part not the variable part

42
Q

Which part of HIV helps it to evade antibodies

A

HIV env spike gp120 resists neutralization

43
Q

How does gp120m the HIV spike molecule, evade neutralisation

A
  1. Large space between spikes prevents Ab crosslinking
  2. Extensive glycosylation masks antibody epitopes
  3. Functionally important parts of the molecule are poorly accessible, CD4 binding site, redundant amino acids are visible to B cell receptor and antibodies.
  4. Huge variation in the redundant amino acids means most antibodies are highly clade specific.
44
Q

Why can large spaces between spikes be a positive and negative thing for viruses

A

Problem for the virus: Allows lots of spaces for ABs to come in and bind the viral spike proteins (i,,e the basis for the ferritin nanoparticle influenza vaccine relies on this)

Benefit for the virus: It means that Abs which bind the viral proteins are too far apart to cross link

So Abs are less efficient

45
Q

What molecule is more glycosylated- gp120 or haeamagglutiin

A

gp120

46
Q

What type of molecule is gp120

A

trimer

47
Q

Do bnAbs exist for HIV?

A

bNabs produced as biological therapeutics can control viral load.

but haven’t yet been developed

48
Q

T/fAntibodies that can cross react with many HIV strains do exist alongside virus in people who control infection.

A

T

49
Q

bNab controls viral load but what is the problem with it

A

That the conserved regions in the gp120 may just mutate (i.e. it might be that they are not necessary for viral function, and that the virus just didn’t have selective pressure before to chage those areas)

50
Q

Differentiate the antigenic drift in human rhinovirus with influenza

A

So the evolutionary process for the common cold virus happened many years ago but there are hundreds of serotypes

With influenza, the process is still happening such that there are still new strains being produced

The reason we cannot vaccinate for the common cold virus is that there are so many serotypes

The reason we cannot vaccinate for flu is that there are new serotypes every year, and many strains cocirculate

51
Q

Outline the problems with the sabin vaccine for polio

A

For the live attenuated Sabin vaccine, administration of all 3 at once resulted in virus interference and poor response to one component.

This meant that you could still be infected with the type against which the body didn’t respond to in the vaccine

However you just needed to adjust the ratios to increase the amount of weedy virus that you injected

One serotype has been eradicated from the world so yu only really need the body to respond to two serotypes now anyway

52
Q

What is teh consequence of antigenic variation of denuge virus

A

Dengue haemorrhagic fever.

53
Q

What causes dengue haemorrhagic fever with regardto antigenic variation

A

Dengue Virus exists as 4 different serotypes.

If you are infected with one serotype, you develop Abs to it

But if a second serotype then infects you, then antibody generated against the previous serotype can bind but not neutralize the new serotype

Instead, the Ab-new serotype complex binds to monocytes via the Fc receptor

And the new serotype can then access the monocytes and replicate inside them!

54
Q

Why does infection of monocytes by a second dengue serotype infection lead to DHF

A
  1. New tropism for the virus to grow in (rapidly grows)

2. Because the monocyte is an APC, then it can release loads of cytokines and cause cytokine storm

55
Q

What does dengue haemorrhagic fever result in

How is it detected

Treatment

A

Leakage of blood plasma from capillaries (due to cytokine storm)

Detected by increase in red cell count and decrease in protein level in blood.

Tendency to severe bruising, and bleeding. Patient deteriorates even after fever drops; shock. Treat with iv fluid replacement.

56
Q

What receptor does measles use and thus what is its tropism

A

MV infects CD150 (=SLAM) positive cells, including memory lymphocytes and erases immunological memory.

57
Q

What is the longer lasting consequence of measles infecion

A

2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.

Rob's Microbiology MCD (6 decks)

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