LA10- Viruses At Mucosal Surface Flashcards
Give 3 gut Mucosal viruses present , 2 respiratory, 3 ugt
Polio, rotavirus, norocirus
Influenza, covid
Hiv, hpv, trichamonasvirus
Which vaccines have been effective for mucosal viruses
Covid, hpv, polio (eradicated)
Which has variable responses
Influenza and rotavirus
Why is it so important hiv develop a vaccine in future
Kills 700,000 people per year
Why has it been difficult
Live attenuated too risky as hiv inserrts into host dna
Inactivated do not havee strong enough immune response
Which type of vaccine is ideally whag you want to tackle mucosal viruses (BECAUSE OF SPECIFIC EFFECTOR HOMING PROGRAMS)
Topical/local/mucosal
Eg because pearwnteral is not effective for gut immune response and you want to evoke strong Siga and cell responses
Are mucosal successful as parentedal
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
Give 4 modes of mucosal vaccination and what effect they have
Orally - suga mammary, gi tract and salivary
Intranasal- ugt, urt and lrt Siga and igG
Rectal - local Siga
Vaginal - local response
Since ugt have no malt where do their local immune responses come from
Associated lymphoid tissue eg inguinal lymph nodes
Which type of vaccine route needs an adjuvant and why
Oral
Gi tract tolerance because of constant Microbiota and food means need stronger evoking
What do adjuvants aim to induce
Release of things like baff, april
Cosrimulatory molecules like b7 on main target dc
What type of b and T cells can be induced by nasal vaccines
Memory
What would both nasal and intramuscular vaccines in future help with covid
Tackle both urt cia nalt to stop flu symptoms and then also lrt protection
What’s the difference between live attenuated and inactivated
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
Give an example of a purified subunit vaccine
Ha influenza
What type of cloning subunit vaccine is hpv
L1 capsid protein is cloned (using yeast cell expression)
and attached to a vlp which is then inserted
What we’re viral vector vaccines originally used for before covid use of adenovirus
Ebola
How does the mrna covid vaccine work
Contained in liposome vesicles which can fuse with a cell membrane and it’s translated so cell presents spike to induce immune response
What are 3 viral vaccines licensed that are mucosal
Polio , rotavirus, influenza (flumist)
Explain the features of polio virus
Non enveloped ssrna with icosahedral capsid
4 capsid proteins line inside v1-4
How is it transmitted
Faecal oral route
Where can it go in some cases of people
Through draining lymph node to bbb and cause paralytic poliomyelitis where paralysis ef of the legs can occur (1%)
Which 2 vaccines are there for polio and whcih is better and why
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
What is the only drawback of the OPV vaccine which means it is rarely used
Small risk of vaccine associated paralytic polio since it isn’t inactivated
Which is more expensive
Ipv
Explain the lifecycle of most enteroviruses but more specifically polio
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
Which protein binds to rna when it’s released crucial to prime for replication
VpG
What is the importance of neutralising antibodies
Stop attachment, endocytosis and uncoating
What genome does triple capsid icosahedral non enveloped rv have
11 piece segmented ds rna
Why is this viral so important
Biggest diarrhoea death of kids under 2
Kills 450k a year
Where do 90% of death occur
Africa or Asia (where vaccine is less effective)
Which 3 antibodies help with initial infection
Anti-vp4 and 7(outer capsid proteins for attachment)
Anti-vp6 (important in endosomal attachment and assembly)
Why is cell mediated response good for rotavirus but limited
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
Which 2 oral vaccines are licensed for rotavirus and what are they specific for
Rotateq (cattle-human hybrid reassortment vaccine)
Rotarix (live attenuated)
For vp 4 and 7
How variable are they in effectiveness
Varies between 70-90% effective and lowest in countries in Africa like Ghana
Why could this be
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)
Why could Microbiota be involved
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
Where is iga acquired from which could affect effectiveness
Breast milk
Which bacteria was showed to effective in inducing iga and th1 responses for RV oral vaccine efficacy
Lactobacillus GG and bifido bb12
Which ssrna icosahedral gut virus has no vaccine
Norovirus
Why is this bad
Leading cause of non bacterial gastroenteritis (with diarrhoea)
Who gets worse symptoms/ chronic with norocirus
Immunocompromised
What else can you think of that will allow better vaccine response/infection response
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
Which bacterial product was found to give polio better adherence and which bacteria in particular
Lps
Bacillus cereus upreg infectivity by 500%
How else were Microbiota in mouse models seen to permit polio infection
Increased replicativity and infectivity eg by 500% in b.cereus colonised nice
Mmtv retrovirus binding to tlr4 with lps on dc induced what
Induced il6 induced il10 (via th2 responses) release which is immunosuppressive so lack of response to virus = way that Microbiota increase infective
Which murine virus was investigated as a stimulator of crohns-like disease with what common snp by cadwell in 2010
Norovirus
Atg16L1 (autophagy snp common)
Causes abnorma autophagy, villus blunting and packaging of paneth cells with reduced amp release
In presence of just the snp whag Happened
No crohns-like pathologies occurred unless virus was present
What sort of paneth cell issues were seen with the mice atg16L1 snp and norovirus present
reduced granule number and size, altered paneth gene exp
What sort of crohns-like pathologies were seen (only with c6 persistent strain)
Deep inflammation into the muscularis and local blood vessels
Blunted villi
Which cytokines response induced by this combination induced rhe villus blunting
TNFa and infy
When antibiotics were given to mice what happened
All the pathologies disappeared
Reduced inflammatory cytokines like ifny and TNFa too
What does this indicate
Dysbiosis induced by Norovirus / Microbiota is responsible for crohns symptoms
What is influenza a structure
Segmented ssrna 8x enveloped
How is it transmitted
Human to human or zooanthroponosis
What 2 events can occur for it to escape immunological memory
Antigenic drift - mutational changes in ag eg HA
Antigenic shift - reassortment of genes majorly in a vector where 2 strains combine
Wht 2 vaccines are there (1 is mucosal) - both provide 3:4 strains
Purified subunit (many strain ag)
Live attenuated flumist nasal spray
How many cases does it prevent
About 50% not so effective
Which secondary bacterial infection can occur with influenza virus which is an issue
Strep pneumoniae
What type of coronavirus is covid 19
Beta
What do normally except 3 a or b coronaviruses cause
Self limiting urt infections
What do the severe ones cause
Severe lrt issues like ards and extra pulmonary problems like diarrhoea
Which is most deadly
Mers (35% death rate)
What is the death rate of covid 19
1%
What are some common comorbidities in people who died with Covid-19
Cvd
Diabetes
Hypertension
Why is diabetes a risk factor
Increased ace2 expression and low ifn response
What happens in old age which could influence inflam state and therefore death widh covid
Dysbiosis (loss of diversity)
Increased proteo bacteria known for inflammatory states - gut lung axis increasing lps??
What sort of inflam states are associated with covid
Low tregs, increased th17,
Which antibody treatment been developed which only works for severe covid
Anti-il6R eg tocilizumab
Where has a nasal vaccine recently been approved but still long to go for mucosal vaccines to covid
China
Which antiinflam given to severe cases
Dexamethasone
Why is il6 significant in ards
Promotes the th17 imbalance and nutrpohilic damage
What marker do iga + cells have which make them impossible to get from iv response
Ccr10 specific to mucosal
Explain the nasal effect on ugt/resp working similar to systemic in that it induced systemic igG and also siga mucosal
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)
What is the success of polio vaccination
Massively eradicated except for places like afghanistan
Explain rotavirus pathogenesis
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
Loss of which immunomodulatory bacteria phyla was associated with ghanaian reduction of rotavirus efficacy and why do you think (vs high proteobac)
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
What types of cell are deficient in mice that are scfa deficient
Plasma cells (they induce class switching eg via aid expression)
What did lei 2019 find about Norovirus and dysbiosis in gnotobiotic pigs infected with human Norovirus
Reduced levels of bifido bacteria and firmicutes which is likely to cause inflammatory effects
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.
Recognition of flagellin
Induced caspases-1 Il1b and il18 maturation
Il1b important for il22 production and release for barrier runctjons
What is ards
Respiratory condition in which an inflammatory state plus cytokines storms will occur - infiltration and destruction of the alveolar-capolly membrane and subsequent pulmonary oedema
