Lecture 22 - Infections in Asthma Flashcards

1
Q

Describe the structure of viruses

A

Nucleocapsid:
• Genome (ss/ds RNA/DNA)
• Protein coat

+/- Envelope

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2
Q

Describe briefly viral life cycles

A

Viruses must use host machinery to replicate
Hence, viruses must infect host cells

Invasion:
1. Adsorbtion of virus to cell
• Non specific charge interactions

  1. Virus binds receptor on host cell
  2. Entry of virus into cell:
    • RME
    • Fusion of host and viral membrane
  3. Uncoating of virus
  4. Replication:
    • Translation of larger polyprotein, followed by cleavage
    • Genome replication
  5. Assembly of virions
  6. Release:
    • Lysis of host cell
    • Budding
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3
Q

Describe the structure of the influenza virion

A
Genome: 8 dsRNA segments
Envelope
HA, NA, & M1 embedded in membrane
Other enzymes:
 • NS-1 etc.
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4
Q

Describe the structure of the RSV virion

A

(Respiratory syncytial virus)

Genome: (-) ssRNA
\+ structural proteins:
 • L: large polymerase protein
 • N: nucleoprotein
 • P: phosphoprotein
Envelope
\+ embedded proteins:
 • G: attachment protein
 • F: fusion protein
 • SH: small hydrophobic protein
 • M: matrix protein
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5
Q

List some viruses that infect the human respiratory tract

A

RSV
• Common cold

Influenza

Rhinoviruses
• Croup

Corona viruses
• SARS

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6
Q

What drives much of the pathology in viral respiratory infections?

A

Host response:
• Over-exuberant neutrophil responses: protease and ROS release
• CTL lysis of infected cells

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7
Q

Describe how respiratory viruses cause harm

A

Alveolar macrophage infection:
• Kills cells
• Cytokine release

Lytic viruses:
• Kills host cells

Non-lytic viruses:
• Induction of cellular immunity & cytokine response

Result:
• Mucous, dead cell debris, & inflammatory cell infiltrate in airways
• Damaged epithelium is more permeable → secondary bacterial infection

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8
Q

Describe the heterogeneity of asthma

A

Many genes involved

Many presentations

Onset can be in childhood or adulthood
• Many children outgrow asthma
• Some only develop it in response to triggers experienced later on in life (e.g. in the workplace)

Many triggers
• Stress, allergens, cold, exercise

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9
Q

What is the prevalence of asthma?

A

1 in 8 children
1 in 10 adults

Mortality decreased considerably since 90’s

Incidence is increasing

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10
Q

Define atopy

A

Tendency to form inflammatory and immune responses to innocuous substances

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11
Q

What are URTI and LRTIs?

A

URTI: upper respiratory tract infection
LRTI: low respiratory tract infection

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12
Q

Define eosinophilia

A

Preponderance of eosinophils in airway tissues and blood

This is a key feature of allergic asthma

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13
Q

Describe the normal response to aeroallergens in the airway

A
  1. Th1 preponderance (over Th2)
  2. Th1 cytokines (IFNgamma) stimulate low level macrophage response
  3. Th1 cytokines privilege low level IgG response
→ physiologic response
 • Don't have mucous hyper secretion
 • No epithelial thickening 
 • No sub-epithelial fibrosis
 • No airway oedema
 • No bronchoconstriction / SM hyperplasia
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14
Q

Describe the allergic response to aeroallergens in the airway

A
  1. Th2 preponderance
  2. Th2 cytokines (IL-4, IL-5, IL-13):
    • Recruit eosinophils and mast cells
    • Stimulate B cells to IgE class switching
  3. Eosinophils release:
    • MBP (major basic protein)
    • ECP (eosinophil cationic protein)
  4. Mast cells release:
    • Histamine
    • Leukotrienes
    • Prostaglandins
→ allergic response
 • Goblet cell hyperplasia
 • Airway oedema
 • Thickened airway epithelium
 • Subepithelial fibrosis
 • Bronchoconstriction / SM hyperplasia
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15
Q

How are microbes sensed in the early stages?

What does this result in?

A

PAMPs on microbes sensed by PRRs

e.g. TLR4 - LPS
TLR3 - dsRNA

Results in the release of pro-inflammatory cytokines, which initiate the response against the pathogen

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16
Q

Outline the hygiene hypothesis

A

Decreased exposure to micro-organisms in early life increases susceptibility to allergic diseases

The immune system requires ‘education’ through exposure to microbes to properly develop

Original study:
• 17,500 children born in 1953 followed
• Prevalence of hay fever at 23 and eczema in first year of life recorded
• Both were less common in children with larger families (older siblings)

17
Q

Describe the importance of early infection

A

In babies:
• Th2 response predominates
• Favours antibody production
• Cytokine responses to early infections eventually favours Th1 responses

Tregs
• Early infection and thus immune responses required for development of Tregs

Antibiotics:
• Can affect the colonisation of the gut with ‘good’ bacteria

NB The benefit of early infection depends on the timing and type of infection
• Type: non-pathogenic: i.e. coughs and colds are beneficial. Pathogenic: e.g. pneumonia, varicella etc.
• Exposure to non-pathogenic bacteria most beneficial
• Favours Th1 over Th2 responses
• Stimulates Tregs

18
Q

Charaterise Th1 and Th2 responses

A

Th1: efficient pathogen clearance

Th2: (parasite immunity), mast cell, IgE, and eosinophil responses

19
Q

What evidence is there for the HH?

A

Developing countries
• Decreased hygiene
• Decreased incidence of allergic and autoimmune diseases
• Migration from country with low hygiene to developed country increases and individuals risk of autoimmune and allergic disease

Murine experiments
• Mice that experience infection in early life less susceptible to autoimmune and allergic disease

Factors that seem to confer benefit:
• Children raised on farms
• Pet ownership
• Having an older sibling

20
Q

Describe the evidence against the HH

A

Association does not prove causation

• Decreasing rates of asthma in some developed countries which are experiencing increasing rates of food allergy

Diversity of microbiome
• May be more important than n° of infections

Many other factors associated with increased asthma risk:
 • Air pollution
 • Household damp
 • Delayed introduction to solids
 • Family history
21
Q

What is the connection between atopy and asthma?

A

Most asthmatics are atopic, but atopy does not necessarily progress to asthma

22
Q

Why are viral respiratory infections particularly troublesome?

A

Recurrent infections are common
• Due to the multiple strains and weak specific immunity (RSV)

Antibiotics are not effective

Infection may affect lung development

23
Q

Which factors confer the greatest risk of persistent asthma?

A
  • LRTI
  • Family Hx
  • Aeroallergen sensitisation
24
Q

Outline likely mechanisms of viral infections and asthma

A

DCs:
• Viral infections interfere with DC maturation and turnover
• This affects tolerance (for which DCs play an important role)

Th2 cytokines:
• Eosinophil and mast cell recruitment
• IgE production

→ tissue damage

25
Q

Which sort of respiratory infections have a greater effect on asthma predisposition?

A

LRTI are more strongly linked with asthma than URTIs

NB Early LRTI may be a sign of predisposition to asthma, not cause

26
Q

Describe how infection fits into the asthma inflammation cycle

A
Inflammation cycle:
1. Environmental triggers stimulate inflammatory response → acute tissue damage:
 • Oedema
 • Smooth muscle hyperplasia
 • Collagen deposition
 • Goblet cell metaplasia
  1. Tissue remodelling
  2. Permanent pathological changes despite resolution of inflammation
  3. Subsequent exposure to environmental triggers; the cycle continues

Role of infection:
• Infection can cause tissue damage that increases the tissue remodelling, further reducing the lung function in the steady state

27
Q

List some risk factors for asthma

A

Too much time indoors
• Decrease vitamin D (decreased immunity)
• Obesity (dyspnoea and inflammation)

C-section delivery
• Decreased initial colonisation with microflora from mother’s birth canal

Cigarette smoking
• Noxious particles in the smoke irritate airways
• Decreased immunity

28
Q

What are asthma exacerbations?

What effect can they have?

How are they treated?

What are the symptoms?

A

Can cause:
• Illness, hospitalisations, death

Therapy:
a. Initially:
 • β2-ADR agonists
 • ICSs
b. Moderate:
 • Antibiotics
 • Nebulised β2-ADR agonists
 • Anti-cholinergic bronchodilators
 • Oral steroids
c. Severe
 • IV bronchodilators & steroids

d. Most severe
• Intubation and mechanical ventilation

Cause of exacerbations:
• 80% caused by viruses, predominantly Rhinovirus

Symptoms:
 • Reduced peak flow
 • Dyspnoea
 • Increased mucous
 • Persistent coughing

Due to:
• Bronchospasm
• Inflammatory cell infiltrate in bronchial tissue
• Persistent viral replication
• Concurrent or sequential bacterial infection

29
Q

Describe cytokine responses to viruses

What is the effect of this response?

A

Viral PAMPs (dsRNA) are agonists for PRRs

This ligation results in sig-transduction that leads to up-regulation of type I IFN

Type I IFN:
• Part of innate immune response
• Produced early by infected epithelial cells

  1. Type I IFN binds to receptor (Janus-family tyrosine kinase) on neighbouring cells
  2. Activation of JAK/STAT pathway
  3. Various anti-viral responses activated in cells
    • eIFa2 etc. → blockage of initiation of translation
    • 2,5-OAS → RNAse L → degradation of viral RNA
  4. Indirect effects:
    • Activation of NK cells
    • Increased Ag presentation by class I pathway
30
Q

Describe recent experiments investigating asthmatic responses to RV infection in bronchial epithelium

A

Experiment:
• Primary bronchial epithelial cells from +/- asthmatic infected with Rhinovirus (RV)
• Basal ICAM levels were the same in each sample (this is the receptor for RV)

Results:
In 'asthmatic' epithelial samples:
 • Higher RV titres
 • Impaired apoptosis
 • Decreased IFN-β production

Furthermore:
• Adding exogenous IFN-β could inhibit the replication of RV

31
Q

List two important ICS drugs for asthma

A

Seretide

Symbicort

32
Q

Compare specific pathogen free and germ free mice

A

Specific pathogen free: free from disease causing microbe

Germ free: free from all microbes

33
Q

Describe recent studies looking at therapeutic IFN-β in RV infection in asthmatics

A

Experimental design:
• 147 individuals with asthma
• Within 24 hrs of cold onset, individuals were randomised to either placebo or inhaled IFN-beta

Results:
In treatment group:
• No effect on symptoms
• Better morning peak flow
• Reduced need for more intense treatment
• ↑ innate immunity markers in blood and sputum