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MB4030 > Influenza > Flashcards

Influenza Flashcards

1
Q

Subtypes of Influenza

A

A,B,C

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2
Q

Most virulent strain of Influenza

A

A

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3
Q

Virus surface antigens

A

Haemagglutinin (H1-18)
Neuraminidase (N1-11)

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4
Q

Antigenic Shift

A
  • Found in Influenza A
  • gene swapping in cells simultaneously co-infected with 2 different influenza viruses
  • human-bird-animal influenza viruses
  • unpredicatable - formation of new strains
  • shifts appear at long intervals - cause epidemics
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5
Q

Antigenic Drift

A
  • found in both influenza A and B
  • point mutation lead to a change in protein coat
  • seasonal variation from year to year
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6
Q

Avian strains with particular concern

A

H5N1
H7N9
(most recently have infected humans)

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7
Q

Reproductive number of Influenza

A

1.3

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8
Q

Clinical Features of Influenza

A
  • abrupt onset, shivering, malaise, headache, aching limbs, temp > 39
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9
Q

How is influenza virus cleared?

A

Innate and adaptive immunity

  • viral RNA recognised by PRRs -> secretion of IFNs and proinflamm cytokines/chemokines
  1. IFNs produced by macrophages, pDCs -> stimualtes ISG expression in neighbouring cells
  2. proinflamm cytokines -> systemic and local inflamm
    - chemokines -> recruit NFs, monocytes, NK cells to airways

-> neutralising Abs on mucousal surfaces to prevent reinfection (CD4 & CD8 T cell response and memory)

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10
Q

How is dsRNA Influenza detected

A
  • infected cell is phagocytosed by macrophages
  • recognition of dsRNA by TLR3
  • induction of NFkB proinflamm cytokines, IFN, IFN-stimulated genes
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11
Q

How is ssRNA Influenza virus detected

A
  • contained within viron
  • released via degradation of viral membrane and capsid within acidified endosomes
  • ssRNA recongised by TLR7 in pDCs
  • TLR7 induces NFkB
  • activation of IRF7
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12
Q

How is viral RNA within cell recognised

A
  • within cytosol, RIG-1 receptors recognise
  • activation of MAVS
  • induction of proinflamm cytokines, IFN type 1
  • M2 ion channel acitvation -> caspase 1 activation
  • release of IL1B and IL-18
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13
Q

Influenza proteins that interfere with PRR signalling and IFN production

A

NSI - expressed in cytoplasm and nucleus, competes with RIG-1 for binding dsRNA -> blocks expression of IFN inducted ISG genes in cells

PB1-F2 - destabilises MAV complex

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14
Q

How to Abs interfere with stages of viral life cycle

A

Anti NA:
1. blocks release of virus from mucins
2. blocks virus release from host cells
3. trigger FcR mediated effector functions (ADCC)
4. activate complement

Anti HA:
1. blocks interaction between HA and host cell receptors -> blocks attachment of virus to host cell
2. blocks fusion of viral and endosomal membranes
3. HA needs to be cleaved into HA1, HA2 subunits to produce infectious particles -> blocks HA cleavage

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15
Q

How are virally infected cells cleared

A

CD8+ T cells

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16
Q

Most immuno-dominant viral proteins for T cell responses

A

Nucleoprotein and matrix protein
(highly conserved across strains)

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17
Q

Humoural immune response

A

B lymphovytes differentiate into Ab-secreting plasma cells

18
Q

Cell-mediated immune response

A

Ag presentation via MHC1 and MHC2 via DCs
-> activation of CD4/8
CD4- Th cells - cytokine release
CD8 - CTL - directly kill

19
Q

Kinetics of Immune Response to a Primary Influenza Infection

A

IFN response is immediate followed by:
- NK cells
- CTLs
- Abs

20
Q

Season Influenza strains

A

H1N1/ H3N2
- strong tropism of URT, trachea, bronchi
- virus attached to ciliated epi cells
- necrosis of resp epi and infiltration of lamina propria by lymphocytes
- leads to rhinitis, paranasal sinusitis, pharyngitis, laryngitis

21
Q

HPAIV

A
  • highly pathogenic avian influenza virus

HPAIV H5N1
- weak tropism for URT, trachea, bronchi
- inefficient infection in humans

22
Q

H5N1

A
  • strong tropism for LRT, brinchioles, alveoli

Binds to
- clara cells lining bronchioles
- alveolar macrophages
- type II pneumocytes lining alveoli

23
Q

H5N1/N7H9 infection

A
  • severe illness complicated by ARDS and MOF
  • high presentation of pneumonia and lymphopenia
  • large no. of macros infected with H5N1 compared to H3N2
  • large production of cytokines (IL1B, IL-6, IL-8, TNFa)
  • large production of chemokines (CCL2 (MCP1), IP10)
24
Q

MCP-1

A

macrophage chemotactic protein 1
(attracts macrophages to infected lung)

25
Q

IL-8

A

attracts NFs to lung

26
Q

NS1 gene mutations in H5N1

A

makes NS1 a more potent inhibitor of IFN production

27
Q

Reason for HPAIV H5N1 severity

A

high replication in alveolar macrophages
induction of secreted pro-inflamm cytokines by infiltrating macrophages

28
Q

Human influenza and associated galactose receptors

A

2,6 galactose receptors

**adaption to recognise this receptor is a requirement for successful infection of human resp cells

29
Q

Avian influenza virus and associated galactose receptors

A

2,3 galactose receptors in GIT

30
Q

Events required to make viruses successfully infect humans

A
  • optimal temp (shift from 40 degs to 37)
  • site of replication from intestinal to resp tract
  • virus receptor specificty changing (alpha 2,3 sialic acid -> alpha 2,6 sialic acid intermediate hosts) *quails and turkeys play a role as they possess sialic acid receptors
31
Q

What strains are highly pathogenic in human and domesticated poultry

A

H5 and H7

*less pathogenic in aquatic bird reservoirs

32
Q

Influenza vaccine 22/23

A

influenza A (H1N1)
influenza A (H3N2)
influenza B (B/victoria lineage)
influnza B (B/yamagata lineage)

33
Q

Why are influenza vaccines sometimes suboptimal

A

antigenic mismatch between vaccine strain and circulating strain

34
Q

Antigenic Sin theory

A
  • flu epitopes encountered in early childhood can permanently shape Ab response to subsequent flu exposures
  • interferes with new response to the new virus
35
Q

Types of vaccines

A

Quadrivalent
- 4 components
- protect against 2nd lineage of B viruses

Live, Attenuated (FluMist) - closest to real thing
- viruses grown in culture (20 degs rather than 37) adapt to their new conditions and become attenuated (weakened version of virus)

Recombinant (FluBlock)
- 1st recombinant DNA tech trivalent influenza vaccine
- produced using insect virus (baculovirus)

36
Q

Criteria for next generation (universal) influenza vaccines

A
  • 75% effectiveness against symptomatic infection
  • protection against group 1 and 2 influenza viruses
  • durable protection that lasts at least a year
  • suitable for all age groups
37
Q

Influenza viral spike (HA) composition

A
  1. Head - sialic acid containing GP receptor - mediates attachement to host cells
  2. Stem - located prox to viral envelope, involved in fusion to host cell membrane
38
Q

What part of spike are neutralising Abs exposed to

A

Head region
- they block virus attachment to cells
- these ABs are strain specific
- don’t neutralise drifting variants due to high mutation rate of HA head
- antigenic drift allows viruses to escape AB response

39
Q

Predominant Memory B cell response of influenza infection is to what part of HA

A

HA Head
- STEM directed Abs less prevalent in serum

40
Q

Conserved region of HA

A

Stem

  • little increased AB affinity (SHM) observed
41
Q

Head vs Stem of anitgens

A

Stem
- not accessible to immune system
- restricted access of Abs
- Abs with broad reactivity to various strains

Head
- epitopes most likely triggered
- immunodominant Abs

*universal flu vaccine needs to trigger conserved STEM region

42
Q

Influenza subunit vaccines

A

use conserved regions of HA stem
- promising candidate for broadly protective vaccines - universal vaccine

MB4030 (11 decks)

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