lecture 22: infections in asthma and COPD Flashcards
1
Q
What are basic aspects of viral structure?
A
- all viruses exist as a nucleocapsid:
- genome (RNA or DNA, ss or ds) + protein coat
- many have a host-derived lipid envelope
- nucleocapsid (+ envelope) = virion
- viruses must use host cell structures and enzymes to replicate, BUT
- there are a few unique viral enzymes, which may be antiviral drug targets
- e.g. influenza virus virions:
- ~200nm diameter
- note spikes of haemagglutinin and neuraminidase surface proteins
- respiratory syncytial virus virions
- the viral genome is complexed with the viral structural proteins L, N and P
2
Q
What are general features of virus replication?
A
- virus may be absorbed to host cell
- virus binds to surface receptor
- virus enters cell and is uncoated
- viral proteins translated and cleaved
- viral genome is replicated
- viral genome may integrate into host
- new virus particles assembled
- new virus particles released
3
Q
What is an introduction to respiratory viruses?
A
- diverse viruses infect the respiratory tract
- rhinoviruses (RV; common cold, many strains)
- influenza (animal hosts, antigenically diverse)
- coronaviruses (SARS; 2003 pandemic)
- no broadly useful vaccines or antivirals available
- at least some pathology is due to host response
- neutrophils release proteases and reactive oxygen species
- cytotoxic T cells lyse infected host cells
4
Q
How do respiratory viruses cause harm?
A
- airway macrophages ingest viruses
- many viruses abortively replicate in macrophages
- release of pro-inflammatory cytokines
- infection curtailed, but some local tissue damage
- influenze and some others are cytolytic
- spread to new cells and hosts
- non-lytic viruses induce cellular and cytokine response
- mucus and dead cells and inflammatory cells clog airways
- damaged airway epithelium becomes more permeable
- bacterial secondary infection is common
5
Q
What is replication of RSV in human bronchial epithelial cells?
A
- pictures showing replication of RSV in human bronchial epithelial cells
- top panel: mock, cells were not infected with virus, but otherwise treated the same, age, confluent, still adherent to plastic surface, shape normal, not clumping
- bottom panel: 23hr picture of RSV, some cells starting to cluster, adjacent infected cells fuse, cells dying, clumping, detaching from surface at 48 hours, by 3 days monolayer is almost completely gone
- RSV is very common among children
6
Q
What is the development of asthma?
A
- all that coughs and wheezes is not asthma
- many children outgrow asthma
- asthma has:
- many triggers (allergy, stress, cold, smoke, infection)
- many genes implicated
- many presentations (allergic, non allergic, post viral wheeze, steroid resistant, + others)
- reasonable treatments but no cure
- some develop asthma later in life (occupational exposures, stress)
7
Q
What is asthma prevalence and mortality?
A
- over 2 million australians have asthma:
- 1 in 8 children, 1 in 10 adults
- 964 deaths in 1989, 378 in 2011 (stable)
- 37,830 hospitalizations in 2010-11
8
Q
What is atopy?
A
- allergy to innocuous substances
9
Q
What is normal flora?
A
- microbes, mostly bacteria, present in certain body sites and are normally harmless
10
Q
What are commensals?
A
- microbes that are normally present and cause no harm, may acquire nutrients from the host
11
Q
What is specific pathogen free/germ free?
A
- free of disease causing/all microbes
12
Q
What is a URTI?
A
- upper respiratory tract infection (often, uncomplicated)
13
Q
What is a LRTI?
A
- lower respiratory tract infection
14
Q
What is eosinophilia?
A
- a key feature of allergic asthma
15
Q
What is IgE?
A
- antibody that mediates allergic reactions
16
Q
What is the appropriate Th1 immune response to aeroallergens in the normal airway?
A
- example of how the immune system should respond to aeroallergens
- CD4 T cells - activated TH1 lymphocyte
- when it encounters an aeroallergen like house dustmite or pet hair → produces TH1 cytokines e.g. IFNgamma, IL-2, TNF-alpha → generally considered beneficial
- activates macrophages
- stimulates production of IgG
- means for airway that things aren’t too bad
- epithelium: normal thickness, no swelling, not a whole lot of mucous
- submucousal glands: not particularly busy
17
Q
What is the Th2 immune deviation to aeroallergens in asthma?
A
- TH2 responses are not all bad, times when you want them, but in asthma bad
- activated TH2 lymphocyte produces a range of TH2 cytokines → IL-4, IL-5, → recruit and activate a lot of cells such as eosinophils (MBP, ECP, leukotrienes, cytokines) , Mast cells (histamine, leukotrienes, cytokines), Plasma cell (IgE)
- these cells have a normal job and function (e.g. helminth infections)
- → airway oedema, goblet cell hyperplasia, subepithelial fibrosis, smooth muscle hyperplasia and/or hypertrophy
- airway becomes remodelled
- airways can become chronically inflamed
- smooth muscle thickening means less responsive to bronchodilators
18
Q
What is virus infection and TLR activation?
A
- pathogen-associated molecular patterns (PAMPs) are conserved microbial patterns
- PAMPs are recognised by pattern recognition receptors (PRRs) on phagocytic cells
- Toll-like receptors (TLRs) are the first responders to microbial infection
- TLR ligands may be:
- extracellular (LPS on gram neg. bacteria - TLR4) or,
- intracellular (viral dsRNA - TLR3)
- activation of phagocytes, release of inflammatory mediators
19
Q
What is the hygiene hypothesis?
A
- a lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases, as the immune system does not develop properly
- the risk of some autoimmune diseases is also increased
- 17,414 children born in march 1958, followed to 23
- incidence of hay fever recorded at age 11 and 23, and eczema in first year of life
- both disorders less common in larger families and with more older siblings
- adjusted for several confounders incl. breastfeeding
- does catching infections from siblings reduce atopy?
- Strachan, D.P. (1989( Br Med
- 3075 (sept 2014; 369 in last year!)
20
Q
What are mechanisms of the hygiene hypothesis?
A
- Th2 immune responses predominate in babies, which promotes antibody production
- cytokine response to early infections leads to overall Th1 response
- Th1 response → efficient pathogen clearance
- Th2 response → more mast cells, eosinophils, IgE
- the infant’s immune system needs stimuli to develop regulatory T cells, which mediate tolerance and dampen immune responses
21
Q
What is more recent work on the HH?
A
- benefit of early infection depends on the type and timing of infection
- more antibiotics now given in early life
- affects colonisation of bowel by “good” bacteria
- exposure to non-pathogenic microbes may give the greatest protection
- favours Th1 over Th2 responses
- stimulates regulatory T cell development
22
Q
What is evidence for the HH?
A
- allergic and autoimmune disorders less common in developing countries
- migration from developing to developed world → greater incidence of these conditions
- early life exposure of mice to infections → a reduced incidence of autoimmune disorders
- children raised on farms are less likely to have allergies and asthma
- pet ownership linked to decreased atopy and asthma
23
Q
What is evidence against the HH?
A
- association does not prove causation
- microbial diversity (host microbiome) may be more important than the number of infections
- asthma rates are decreased in some developed nations while food allergy continues to rise
- many factors linked to increased asthma and allergy:
- delayed introduction to solids
- air pollution
- household damp and airborne moulds family history
- family history
24
Q
What is the relationship between early respiratory infections and asthma?
A
- most asthmatics are atopic, but only some atopic children progress to asthma
- viral infections particularly relevant, as
- weak specific immunity (RSV) and large numbre of strains (RVs, flu) → re-infections common
- viral infections are not treatable with antibioitcs
- early virus infection may affect lung development
- long term birth cohort studies: wheeze is common, but LRTI + aeroallergen sensitization + family Hx of asthma = → greatest risk of persistent asthma
25
Q
What are likely mechanisms related to respiratory infections and their relationship with asthma onset?
A
- viral infection alters normal maturation and turnover of dendritic cells → altered tolerance
- more severe LRTIs (e.g. RSV) more strongly linked to asthma than uncomplicated URTIs
- Th2 cytokines stimulate IgE production
- damaged tissue → inflammatory cell recruitment
- early respiratory infection may be a sign of predisposition to asthma, and not a cause
- symptoms are initially intermittent; airway oedema and constriction
- infection worsens inflammation
- antiviral and allergic cytokines amplify inflammation
- persistent inflammation → repeated cycles of tissue repair and remodelling
- lung structures may be irreversibly damaged
26
Q
What are some of the many risk factors for asthma?
A
- inactivity/too much time indoors
- too little vitamin D → impaired immunity obesity → dyspnoea and inflammation
- C-section delivery → slight increase in asthma (early colonization by mother’s flora)
- cigarette smoke exposure irritates airways and reduces protective immune responses
- some risk factors overlap with the HH
27
Q
What are important public health messages?
A
- “dirt is good”… to some extent!
- not all micro-organisms are harmful, BUT
- little evidence for benefits of probiotics, and
- it’s important to avoid serious infections
- ear and throat infections, pneumonia
- vaccination significantly decreases occurence of infections that can kill or have permanent, serious consequences
- whooping cough, measles, mumps, varicella
- asthma is fairly treatable - for most patients
28
Q
What are asthma exacerbations?
A
- cause illness, hospitalisation and death
- initial treatment: inhaled beta2-agonists and steroids
- moderate cases: antibiotics, nebulized beta2-agonists and anti-cholinergic bronchodilators, plus oral steroids
- severe cases: i.v. bronchodilators and steroids, possibly adrenaline
- most severe cases: intubation and mechanical ventilation
- hard to detect viruses in AE by cell culture
- PCR indicated that ~80% of AE are caused by viruses, mostly rhinovirus (RV)
- 76 cohabitating couples (1 with atopic asthma)
- daily respiratory diary, 2x daily peak flow
- nasal aspirates taken fortnightly for RV culture
- asthmatics don’t more colds, but longer lasting and worse colds
29
Q
What are symptoms of asthma exacerbations?
A
- reduced peak flow, dyspnoea
- increased mucus and constricted airways
- persistent coughing affects eating and sleeping
- reflects…
- excessive influx of inflammatory cells
- dysregulated leukocyte activation and resolution
- ? persistent viral replication/presence in LRT
- concurrent or sequential bacterial infection
30
Q
What does viral infection induce?
A
- dsRNA is present either in viral genome or as a replicative intermediate → induces IFNs
- IFN-alpha/beta produced early by infected epithelial cells and some leukocutes
- IFN-gamma produced later by lymphocytes
- IFN binding to receptor → Janus-family tyrosine kinase → phosphorylation of STAT proteins
31
Q
What are the diverse antiviral effects of IFN?
A
- direct interference with viral replication
- degrades viral RNA
- blocks initiation of translation
- indirect antiviral effect
- activation of NK cells and macrophages
- increases antigen presentation and MHC class I
- IFNs used clinically to treat hepatitis
- IFNs cause fever and other flu-like symptoms
32
Q
Why do asthmatics get worse and longer colds?
A
- primary bronchial epithelial cells grown from those +/- asthma, infected with rhinovirus (RV)
- both types have similar basal ICAM-1 levels
- asthmatic cells have higher RV titres and delayed lysis, due to impaired apoptosis
- asthmatic cells produced less IFN-beta
- adding IFN-beta to infected asthmatic cells induced apoptosis and reduced viral replication
33
Q
What research has been done on IFN-beta to treat asthma exacerbations?
A
- 147 steroid-using asthmatics (18-65 years) with a history of viral exacerbations
- within 24 hr of cold onset, randomized to 14 d of inhaled IFN-beta, or placebo
- IFN-beta did not reduce asthma symptoms, but treated subjects had:
- better morning peak flow
- less need for more intense treatment
- increased innate immunity markers in blood and sputum
34
Q
summary
A
- the hygiene hypothesis is well supported but controversial
- types and timing of infection and microbial diversity important
- asthma is a variable disease with multiple, overlapping causes
- respiratory virus infections are involved in onset and exacerbation of asthma
- mechanisms are complex but involve:
- altered signalling by infected cells
- altered recruitment and activation of immune cells
- dirt can be good… sometimes
35
Q
What are prospects for asthma treatment, and prevention?
A
- Th2/IgE blockade is of limited benefit in established asthma
- can early anti-Th2 treatment stop asthma in high risk children?
- promotion of IFN responses in early infection
- a vaccine for RSC - one day?
- deliberate infection with helminths (helminth infection inversely correlates with allergies)
36
Q
What are the signalling events once TLRs are activated?
A
- MyD88: myeloid differentiation primary response protein →
- IRAKs: IL-1 receptor associated kinases +
- TRAF6: tumour necrosis factor receptor associated factor
- NFkB is uncoupled from its inhibitors, translocates to the nucleus and initiates transcription of proinflammatory cytokines
