LA10- Viruses At Mucosal Surface Flashcards

1
Q

Give 3 gut Mucosal viruses present , 2 respiratory, 3 ugt

A

Polio, rotavirus, norocirus

Influenza, covid

Hiv, hpv, trichamonasvirus

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2
Q

Which vaccines have been effective for mucosal viruses

A

Covid, hpv, polio (eradicated)

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3
Q

Which has variable responses

A

Influenza and rotavirus

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4
Q

Why is it so important hiv develop a vaccine in future

A

Kills 700,000 people per year

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5
Q

Why has it been difficult

A

Live attenuated too risky as hiv inserrts into host dna
Inactivated do not havee strong enough immune response

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6
Q

Which type of vaccine is ideally whag you want to tackle mucosal viruses (BECAUSE OF SPECIFIC EFFECTOR HOMING PROGRAMS)

A

Topical/local/mucosal
Eg because pearwnteral is not effective for gut immune response and you want to evoke strong Siga and cell responses

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7
Q

Are mucosal successful as parentedal

A

No, still weakly immunogenic compared to parentedal
Plus parentedal can be used for resp tract and ugt response because they get 50% igG from systemic sources

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8
Q

Give 4 modes of mucosal vaccination and what effect they have

A

Orally - suga mammary, gi tract and salivary

Intranasal- ugt, urt and lrt Siga and igG

Rectal - local Siga

Vaginal - local response

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9
Q

Since ugt have no malt where do their local immune responses come from

A

Associated lymphoid tissue eg inguinal lymph nodes

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10
Q

Which type of vaccine route needs an adjuvant and why

A

Oral

Gi tract tolerance because of constant Microbiota and food means need stronger evoking

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11
Q

What do adjuvants aim to induce

A

Release of things like baff, april

Cosrimulatory molecules like b7 on main target dc

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12
Q

What type of b and T cells can be induced by nasal vaccines

A

Memory

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13
Q

What would both nasal and intramuscular vaccines in future help with covid

A

Tackle both urt cia nalt to stop flu symptoms and then also lrt protection

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14
Q

What’s the difference between live attenuated and inactivated

A

Attenuated is where purified virus incubates with eg monkey cells and adapts to infect those cells so not as easy infecting human cells

Inactivated means they are killed

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15
Q

Give an example of a purified subunit vaccine

A

Ha influenza

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16
Q

What type of cloning subunit vaccine is hpv

A

L1 capsid protein is cloned (using yeast cell expression)
and attached to a vlp which is then inserted

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17
Q

What we’re viral vector vaccines originally used for before covid use of adenovirus

A

Ebola

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18
Q

How does the mrna covid vaccine work

A

Contained in liposome vesicles which can fuse with a cell membrane and it’s translated so cell presents spike to induce immune response

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19
Q

What are 3 viral vaccines licensed that are mucosal

A

Polio , rotavirus, influenza (flumist)

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20
Q

Explain the features of polio virus

A

Non enveloped ssrna with icosahedral capsid

4 capsid proteins line inside v1-4

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21
Q

How is it transmitted

A

Faecal oral route

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22
Q

Where can it go in some cases of people

A

Through draining lymph node to bbb and cause paralytic poliomyelitis where paralysis ef of the legs can occur (1%)

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23
Q

Which 2 vaccines are there for polio and whcih is better and why

A

Inactivated parenteral IPV
Oral live attenuated OPV

OPV is better as it induces both Siga and systemic igG responses eventually

IPV induces only igG systemically which can help only if it spreads through draining lymph node

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24
Q

What is the only drawback of the OPV vaccine which means it is rarely used

A

Small risk of vaccine associated paralytic polio since it isn’t inactivated

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25
Q

Which is more expensive

A

Ipv

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26
Q

Explain the lifecycle of most enteroviruses but more specifically polio

A

Cd155 receptor for polio induced endocytosis
Uncoatinf in acidic endosome causes +ve rna to be released
Rna then translated to form polyprotein processed and capsid proteins start to assembly

The rna is replicated via the newly translated rep machinery eg protein polio 3A by rna dep rna pol = replication

Then assembles and lyric or non lyric release

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27
Q

Which protein binds to rna when it’s released crucial to prime for replication

A

VpG

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28
Q

What is the importance of neutralising antibodies

A

Stop attachment, endocytosis and uncoating

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29
Q

What genome does triple capsid icosahedral non enveloped rv have

A

11 piece segmented ds rna

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30
Q

Why is this viral so important

A

Biggest diarrhoea death of kids under 2
Kills 450k a year

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31
Q

Where do 90% of death occur

A

Africa or Asia (where vaccine is less effective)

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32
Q

Which 3 antibodies help with initial infection

A

Anti-vp4 and 7(outer capsid proteins for attachment)

Anti-vp6 (important in endosomal attachment and assembly)

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33
Q

Why is cell mediated response good for rotavirus but limited

A

Doesn’t work effectively without Siga too
Works through iec cd8 recognition of mhc1 and killing via FAs, perforin and granzymes

Also the cell response has limited memory

34
Q

Which 2 oral vaccines are licensed for rotavirus and what are they specific for

A

Rotateq (cattle-human hybrid reassortment vaccine)
Rotarix (live attenuated)

For vp 4 and 7

35
Q

How variable are they in effectiveness

A

Varies between 70-90% effective and lowest in countries in Africa like Ghana

36
Q

Why could this be

A

Sanitation, malnutrition, birth mode, breastfeeding , antibiotics

Ie Microbiota and dysbiosis
If malnutritioned you’re likely having a lower diversity which affects your immune maturation (shown from gf mice)

37
Q

Why could Microbiota be involved

A

They shape the immune system and also the barrier to rv
Eg if you have persistent infections, not breastfed, antibiotic use this can all disrupt the barrier eg thin mucus,Amps , cell permeability etc

Plasma cell survival induced by TSLP- baff and April

These are the first line of defence = poor vaccine performance

38
Q

Where is iga acquired from which could affect effectiveness

A

Breast milk

39
Q

Which bacteria was showed to effective in inducing iga and th1 responses for RV oral vaccine efficacy

A

Lactobacillus GG and bifido bb12

40
Q

Which ssrna icosahedral gut virus has no vaccine

A

Norovirus

41
Q

Why is this bad

A

Leading cause of non bacterial gastroenteritis (with diarrhoea)

42
Q

Who gets worse symptoms/ chronic with norocirus

A

Immunocompromised

43
Q

What else can you think of that will allow better vaccine response/infection response

A

Pigr upregulation through the nfkb pathway via il17/ other cytokines

Baff/April which are induced by adjuvants can be induced by tslp- mediated Microbiota release

44
Q

Which bacterial product was found to give polio better adherence and which bacteria in particular

A

Lps

Bacillus cereus upreg infectivity by 500%

45
Q

How else were Microbiota in mouse models seen to permit polio infection

A

Increased replicativity and infectivity eg by 500% in b.cereus colonised nice

46
Q

Mmtv retrovirus binding to tlr4 with lps on dc induced what

A

Induced il6 induced il10 (via th2 responses) release which is immunosuppressive so lack of response to virus = way that Microbiota increase infective

47
Q

Which murine virus was investigated as a stimulator of crohns-like disease with what common snp by cadwell in 2010

A

Norovirus

Atg16L1 (autophagy snp common)

Causes abnorma autophagy, villus blunting and packaging of paneth cells with reduced amp release

48
Q

In presence of just the snp whag Happened

A

No crohns-like pathologies occurred unless virus was present

49
Q

What sort of paneth cell issues were seen with the mice atg16L1 snp and norovirus present

A

reduced granule number and size, altered paneth gene exp

50
Q

What sort of crohns-like pathologies were seen (only with c6 persistent strain)

A

Deep inflammation into the muscularis and local blood vessels

Blunted villi

51
Q

Which cytokines response induced by this combination induced rhe villus blunting

A

TNFa and infy

52
Q

When antibiotics were given to mice what happened

A

All the pathologies disappeared
Reduced inflammatory cytokines like ifny and TNFa too

53
Q

What does this indicate

A

Dysbiosis induced by Norovirus / Microbiota is responsible for crohns symptoms

54
Q

What is influenza a structure

A

Segmented ssrna 8x enveloped

55
Q

How is it transmitted

A

Human to human or zooanthroponosis

56
Q

What 2 events can occur for it to escape immunological memory

A

Antigenic drift - mutational changes in ag eg HA

Antigenic shift - reassortment of genes majorly in a vector where 2 strains combine

57
Q

Wht 2 vaccines are there (1 is mucosal) - both provide 3:4 strains

A

Purified subunit (many strain ag)

Live attenuated flumist nasal spray

58
Q

How many cases does it prevent

A

About 50% not so effective

59
Q

Which secondary bacterial infection can occur with influenza virus which is an issue

A

Strep pneumoniae

60
Q

What type of coronavirus is covid 19

A

Beta

61
Q

What do normally except 3 a or b coronaviruses cause

A

Self limiting urt infections

62
Q

What do the severe ones cause

A

Severe lrt issues like ards and extra pulmonary problems like diarrhoea

63
Q

Which is most deadly

A

Mers (35% death rate)

64
Q

What is the death rate of covid 19

A

1%

65
Q

What are some common comorbidities in people who died with Covid-19

A

Cvd
Diabetes
Hypertension

66
Q

Why is diabetes a risk factor

A

Increased ace2 expression and low ifn response

67
Q

What happens in old age which could influence inflam state and therefore death widh covid

A

Dysbiosis (loss of diversity)
Increased proteo bacteria known for inflammatory states - gut lung axis increasing lps??

68
Q

What sort of inflam states are associated with covid

A

Low tregs, increased th17,

69
Q

Which antibody treatment been developed which only works for severe covid

A

Anti-il6R eg tocilizumab

70
Q

Where has a nasal vaccine recently been approved but still long to go for mucosal vaccines to covid

A

China

71
Q

Which antiinflam given to severe cases

A

Dexamethasone

72
Q

Why is il6 significant in ards

A

Promotes the th17 imbalance and nutrpohilic damage

73
Q

What marker do iga + cells have which make them impossible to get from iv response

A

Ccr10 specific to mucosal

74
Q

Explain the nasal effect on ugt/resp working similar to systemic in that it induced systemic igG and also siga mucosal

A

Siga mucosal- produces cells with ccr10 and a4b1 which are mucosal specific eg iga only has ccr10 and a4b1 can bind vcam on bronchi

Systemic receptors also induced in nalt eg l-selectin and ccr7 to provide systemic igG (ugt and resp tract)

75
Q

What is the success of polio vaccination

A

Massively eradicated except for places like afghanistan

76
Q

Explain rotavirus pathogenesis

A

Attachment through vp4 protein and endocytosis
Subsequent release from infected absorptive cell causes cell death

Villus atrophy

Malabsorption means drexreased water and electrolyte absorption = diarrhoea

77
Q

Loss of which immunomodulatory bacteria phyla was associated with ghanaian reduction of rotavirus efficacy and why do you think (vs high proteobac)

A

Bacteroidetes were much lower - this reduces beneficial scfa effects for strengthening epi barriers etc
Also drive expansion of th1 cells via tbet hyperacetylarion but then not too overwhelming as they induce tregs too - help with the progression of infection

78
Q

What types of cell are deficient in mice that are scfa deficient

A

Plasma cells (they induce class switching eg via aid expression)

79
Q

What did lei 2019 find about Norovirus and dysbiosis in gnotobiotic pigs infected with human Norovirus

A

Reduced levels of bifido bacteria and firmicutes which is likely to cause inflammatory effects

80
Q

How is nlrc4/tlr5 Microbiota interactions important for rotavirus protection showing benefits of commensals - mouse model studied this and found induction was able to prevent or eliminate infection.

A

Recognition of flagellin

Induced caspases-1 Il1b and il18 maturation
Il1b important for il22 production and release for barrier runctjons

81
Q

What is ards

A

Respiratory condition in which an inflammatory state plus cytokines storms will occur - infiltration and destruction of the alveolar-capolly membrane and subsequent pulmonary oedema