Lecture 22 - Infections in Asthma Flashcards
Describe the structure of viruses
Nucleocapsid:
• Genome (ss/ds RNA/DNA)
• Protein coat
+/- Envelope
Describe briefly viral life cycles
Viruses must use host machinery to replicate
Hence, viruses must infect host cells
Invasion:
1. Adsorbtion of virus to cell
• Non specific charge interactions
- Virus binds receptor on host cell
- Entry of virus into cell:
• RME
• Fusion of host and viral membrane - Uncoating of virus
- Replication:
• Translation of larger polyprotein, followed by cleavage
• Genome replication - Assembly of virions
- Release:
• Lysis of host cell
• Budding
Describe the structure of the influenza virion
Genome: 8 dsRNA segments Envelope HA, NA, & M1 embedded in membrane Other enzymes: • NS-1 etc.
Describe the structure of the RSV virion
(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
List some viruses that infect the human respiratory tract
RSV
• Common cold
Influenza
Rhinoviruses
• Croup
Corona viruses
• SARS
What drives much of the pathology in viral respiratory infections?
Host response:
• Over-exuberant neutrophil responses: protease and ROS release
• CTL lysis of infected cells
Describe how respiratory viruses cause harm
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
Describe the heterogeneity of asthma
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
What is the prevalence of asthma?
1 in 8 children
1 in 10 adults
Mortality decreased considerably since 90’s
Incidence is increasing
Define atopy
Tendency to form inflammatory and immune responses to innocuous substances
What are URTI and LRTIs?
URTI: upper respiratory tract infection
LRTI: low respiratory tract infection
Define eosinophilia
Preponderance of eosinophils in airway tissues and blood
This is a key feature of allergic asthma
Describe the normal response to aeroallergens in the airway
- Th1 preponderance (over Th2)
- Th1 cytokines (IFNgamma) stimulate low level macrophage response
- 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
Describe the allergic response to aeroallergens in the airway
- Th2 preponderance
- Th2 cytokines (IL-4, IL-5, IL-13):
• Recruit eosinophils and mast cells
• Stimulate B cells to IgE class switching - Eosinophils release:
• MBP (major basic protein)
• ECP (eosinophil cationic protein) - Mast cells release:
• Histamine
• Leukotrienes
• Prostaglandins
→ allergic response • Goblet cell hyperplasia • Airway oedema • Thickened airway epithelium • Subepithelial fibrosis • Bronchoconstriction / SM hyperplasia
How are microbes sensed in the early stages?
What does this result in?
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
Outline the hygiene hypothesis
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)
Describe the importance of early infection
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
Charaterise Th1 and Th2 responses
Th1: efficient pathogen clearance
Th2: (parasite immunity), mast cell, IgE, and eosinophil responses
What evidence is there for the HH?
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
Describe the evidence against the HH
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
What is the connection between atopy and asthma?
Most asthmatics are atopic, but atopy does not necessarily progress to asthma
Why are viral respiratory infections particularly troublesome?
Recurrent infections are common
• Due to the multiple strains and weak specific immunity (RSV)
Antibiotics are not effective
Infection may affect lung development
Which factors confer the greatest risk of persistent asthma?
- LRTI
- Family Hx
- Aeroallergen sensitisation
Outline likely mechanisms of viral infections and asthma
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
Which sort of respiratory infections have a greater effect on asthma predisposition?
LRTI are more strongly linked with asthma than URTIs
NB Early LRTI may be a sign of predisposition to asthma, not cause
Describe how infection fits into the asthma inflammation cycle
Inflammation cycle: 1. Environmental triggers stimulate inflammatory response → acute tissue damage: • Oedema • Smooth muscle hyperplasia • Collagen deposition • Goblet cell metaplasia
- Tissue remodelling
- Permanent pathological changes despite resolution of inflammation
- 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
List some risk factors for asthma
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
What are asthma exacerbations?
What effect can they have?
How are they treated?
What are the symptoms?
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
Describe cytokine responses to viruses
What is the effect of this response?
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
- Type I IFN binds to receptor (Janus-family tyrosine kinase) on neighbouring cells
- Activation of JAK/STAT pathway
- Various anti-viral responses activated in cells
• eIFa2 etc. → blockage of initiation of translation
• 2,5-OAS → RNAse L → degradation of viral RNA - Indirect effects:
• Activation of NK cells
• Increased Ag presentation by class I pathway
Describe recent experiments investigating asthmatic responses to RV infection in bronchial epithelium
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
List two important ICS drugs for asthma
Seretide
Symbicort
Compare specific pathogen free and germ free mice
Specific pathogen free: free from disease causing microbe
Germ free: free from all microbes
Describe recent studies looking at therapeutic IFN-β in RV infection in asthmatics
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
