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Infection and Immunity > Viral infections - Influenza > Flashcards

Viral infections - Influenza Flashcards

1
Q

orthomyxovirus

A

[family of negative-sense RNA viruses that cause influenza]

ssRNA

Enveloped

Recognises sialic acid receptors

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2
Q

important viral components

A

antigenic

non-structural protein

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3
Q

3 types of envelope proteins

A

Hemagglutinin (HA)
- Functions in attachment and penetration
- Receptor = sialic acid

Neuraminidase (NA)
- Cleaves sialic acid from glycoconjugates
- Facilitates elution of progeny virions from
infected cells

M2 - functions in uncoating and virus maturation

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4
Q

replication cycle

A

adsorption

endocytosis and fusion

uncoating

RNA -> mRNA -> siRNAs

packaging and budding

release

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5
Q

what is haemagglutinin (H) required for?

A

attaching influenza virus to cell surface

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6
Q

what is neuraminidase (N) required for?

A

efficient release of new virions from infected cells

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7
Q

Haemagglutinin structure

A

Protein

Comprised of 2 domains:
- Globular head -> binds to cell surface
receptor sialic acid
- Fibrous stem

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8
Q

Neuraminidase function

A

[protein/enzyme]

breaks down sialic acid receptor on cell surface

Many pathogens have acquired neuraminidases to facilitate infection/propagation

Once sialic acid is removed from the receptor by neuraminidase, haemagglutinin protein can no longer bind

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9
Q

Response to influenza infection - initial response

A

[innate]

NFkB transcription

Leads to pro-inflammatory cytokine gene expression of TNFα, IFNβ and IL-8

Chemokines and cytokines produced increase inflammatory response by attracting NK, B and T cells to infection site

continue to produce more inflammatory cytokines (IL-1β, TNFα, IL-18, IFN-gamma, IFNα/β) to keep Th1 response cycle going

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10
Q

Response to influenza infection - long-term response

A

IFN-gamma boots chemokine gene expression, activation of macrophages, antigen presentation and continual development of specific cell-mediated immunity

Th2 response

T cell stimulation

Antigen presentation

B cell maturation

Antigen-specific IgG production -> long term protection

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11
Q

types of influenza virus

A

A,B,C,D

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12
Q

influenza A - host range

A

humans, pigs, horses, birds, marine animals

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13
Q

influenza A - epidemiology

A

antigenic shift and drift

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14
Q

influenza A - clinical features

A

may cause pandemics with significant mortalities in affected young people

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15
Q

influenza A - genome

A

8 gene segments

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16
Q

influenza A - structure

A

10 viral proteins

M2 = unique

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17
Q

influenza B - host range

A

humans only

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18
Q

influenza B - epidemiology

A

antigenic drift only

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19
Q

influenza B - clinical features

A

severe disease

generally confined to elderly or high-risk

pandemics not seen

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20
Q

influenza B - genome

A

8 gene segments

21
Q

influenza B - structure

A

11 viral proteins

NB unique

22
Q

influenza C - host-range

A

humans and pigs

23
Q

influenza C - epidemiology

A

antigenic drift only

24
Q

influenza C - clinical features

A

mild disease

common in children

without seasonality

25
Q

influenza C - genome

A

7 gene segments

26
Q

influenza C - structure

A

9 viral proteins

HEF = unique

27
Q

Influenza A - sub-types

A

Based on 2 proteins on the surface of the virus
1. Hemagglutinin (H)
2. Neuraminidase (N)

18 different hemagglutinin (H1-H18)

11 different neuraminidase (N1-N11)

H1N1 and H3N2 = sub-type of influenza A found in people

IgG antibody will only recognise the 1 sub-type of H or N it was generated against

28
Q

Influenza A - antigenic drift

A

Gradual accumulation of amino acid mutations that allow the hemagglutinin to escape neutralising antibodies

Epidemic strains of influenza are thought to have changes in 3 or more antigenic sites

Seasonal influenza

29
Q

what is antigenic drift?

A

reduced ability of circulating antibodies to recognise new virus

30
Q

Genetic shuffling - reassortment

A

Entire genes encoding a different H or N sub-types is incorporated into the new virus

Often occurs in animal hosts which are co-infected with 2 or more strains of influenza

31
Q

Seasonal influenza

A

variant of previous stain

most of population will have partial immunity

ANTIGENIC DRIFT

32
Q

Pandemic influenza - antigenic shift

A

Occurs when new strain of virus forms, often originating from another species

No immune history -> no natural protection

Impossible to predict nature of new strain or when it will emerge

Can be highly pathogenic and result in high rates of mortality

No distinction between “at-risk” groups and healthy adults

33
Q

what’s the standard influenza vaccine?

A

trivalent inactivated vaccine (TIV), intramuscular

34
Q

issues with egg propagation?

A

time consuming

expensive

incompatible with propagating high pathogen avian influenza strains

35
Q

vaccine production

A

co-infection of chicken eggs with A/PR.8/34 and epidemic strains

re-assortment and selection of seed strain

propagation of seed strain in chicken effs

purification of harvested vaccine virus by zonal centrifugation

treatment with formaldehyde -> inactivated vaccine

treatment with ethyl ether -> split vaccine

treatment with detergents and purification of HA -> subunit vaccine

36
Q

Adamantanes - M2 inhibitors

A

[Amantadine; Rimantadine]

interfere with function of transmembrane domain of M2 protein of influenza A viruses

decrease release of influenza A viral particles into host cell

block H+ channels that allow uncoating after endocytosis

37
Q

problem with adamantanes?

A

Rapid development of resistance in 30% of treated patients (2-5 days)

90% of clinical isolates in the US show resistance to amantadine in 2005

Wide range of side effects and toxicity

38
Q

Rimantadine

A

less toxic alternative to amantadine (similar structure and MoA)

39
Q

Neuraminidase inhibitors

A

[Oseltamivir; Zanamivir]

Competitive inhibitors that compete with natural receptors for access to neuraminidase active site

40
Q

Neuraminidase inhibitors - advantages

A

Active against all strains of influenza (A, B, C) and all serotypes (including H5N1 and H1N1)

41
Q

Neuraminidase inhibitors - development

A

Chemical mechanism of influenza neuraminidase was known (should be same for all sub-types of N-protein)

Inhibitors were initially developed to mimic transition state structure of sialic acid
- Not selective for influenza neuraminidase
- Also inhibited human neuraminidase
- Original inhibitors were not very potent (micromolar)

42
Q

why was the X-ray crystal structure of influenza neuraminidase important?

A

showed it had transition state inhibitor Neu5Ac2en bound in the enzyme

Key discoveries from this structure:
- Large empty pocket of space near OH-4
- group of sialic acid (unique to influenza
neuraminidase)
- Acidic amino acid (glutamate) that formed
a H bond with OH-4 group

** Low nM inhibitor
** High specificity

43
Q

Zanamivir

A
  • Guanadino group was introduced to replace OH-4 group
    • Compound now selective for influenza neuraminidase over human neuraminidase as large guanadino group can fit into empty pocket
    • Guanadino group formed H bond with glutamate amino acid
    • Potency of compound improved over 1000-fold

Half-life = 2.5-5 hours

Very few side effects as space is only present in viral particles

Low bioavailability -> has to be inhaled (big drawback) -> Structure = very hydrophilic

44
Q

Oseltamivir - modifications

A

Replaced hydroxyl sidechain with a hydrocarbon sidechain to improve lipophilicity

Removed guanadino group to improve lipophilicity

Converted carboxylic acid -> ester to improve lipophilicity

Removed ring oxygen to improve stability (also allowed double bond to be moved -> resembles transition-state)

45
Q

influenza management - do we use drugs or vaccines?

A

Vaccines provide protection against infection but need to be produced ahead of time
- Specific vaccine is required for each serotype of influenza

Drugs don’t give long-lasting protection against infection but are active against all strains and serotypes
- Can be stored for prolonged periods -> stockpiled
- Resistance is becoming more of a problem

46
Q

influenza management - seasonal

A

Vaccine = first line of defense

When actual strain differs from that predicted (to which vaccines were produced), the vaccines may still provide limited protection, but anti-viral drugs become more important for treatment and management

Can also result in small epidemic outbreaks as a result

Use of anti-virals “non-risk” groups = largely for relief of symptoms

47
Q

influenza management - pandemic

A

Neuraminidase inhibitors = first line of defense (not possible to have vaccine prepared)

Role of anti-influenza drug changes
- “life-saving” rather than for relief of symptoms

Will be administered more widely for prophylaxis in an effort to reduce the spread of infection

48
Q

why was Oseltamivir only specific the viral particles?

A

Very hydrophobic -> causes amino acids to move and re-arrange

Creates pocket in enzyme (not predicted from crystal structure)
- Only occurs in viral proteins

49
Q

why was it important for Oseltamivir to not need the guanadino group?

A

improves bioavailability while keeping selectivity

therefore can be administered orally

Infection and Immunity (17 decks)

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