Lecture 22 - Infections in Asthma and COPD Flashcards
All viruses exists as a _______
Nucleocapsid
Genome + protein coat
Many have a host-derived..
lipid envelopes
What are the general features of virus replication
Viruses may be adsorbed to host cell
virus binds to surface receptor
Virus enters cell and is uncoated (genome is exposed)
Viral proteins translated and cleaved
Viral genome is replicated
New virus particles assembled
New virus particles released
neurominidase is a viral enzyme required for …..
the virus to leave the host cell - targwtted by tamifllu
What are the diverse viruses that infect the respiratory tract?
Rhinoviruses
Influtenza
RSV
Coronaviruses
Why is there no broadly useful vaccines or antiviral available for resp infection
The diverse ypes of viruses have different ways of infection and many strains (which vary year to year)
also doesn’t deal with the host reposen
At least some viral pathology is due to host response, how?
neutrophils release proteases and ROS
cytotoxic T cells lyse infected host cells
How do respiratory viruses cause harm
Airway macrophages ingest viruses. Many viruses abortively, replicate in macrophages
This causes:
- release of pro-inflammatory cytokines
- infection curtailed, but some local tissue damage
Influenza and some others are cytolitic - spread new cells and hosts
Non-lytic viruses induce cellular and cytokine resp.
Mucus + dead cells + inflammatory cells clog airways
Damaged airway epithelium becomes MORE PERMEABLE
BACTERIAL secondary infection is common
RSV is very common amongst…
childern
Asthma has many….
Triggers (allergy, stress, cold, infection)
Genes
Presentations
Treatments (but no cure)
over _ million Australians have asthma
2 million
1/8 children
1/10 adults
What does atopy mean?
allergy to innocuous substances
What are commonsals?
microbe that is normally present and causes no harm
What is more complicated usually URTI or LRTI?
Lower resp. tract infection
Eosinophilia is a key feature of …
allergic asthma
What is the appropriate Th1 immune response to aeroallergens in the normal airway?
The activated Th1 lymphocyte produces cytokines (IFN, TNF-a) which stimulate macrophages
In asthma what is the Th2 immune deviation?
ACtivation of Eosinophils, Mast cells (histamine), Plasma cells (IgE) cause inflammation and mucous accumulation which clogs the airway - can also remodel and make smooth muscle thicker
TLR is a type of…
pattern (PAMP) recognition - first responders
TLR ligands may be:
extracellular
intracellular
Responsible for activation of phagocytes, release of inflammatory mediators
What is the hygiene hypothesis? (HH)
a lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases, as the immune system does not properly develop
Risk of autoimmune disease is also increased
HH was identified via…
studies showing that eczema and hay fever were less common in larger families and with more older siblings
What is the proposed mechanism of HH?
Th2 immune responses predominate in babies, which promotes antibody production
Cytokine response to early infections leads to overall Th1 response:
- efficient pathogen clearance
- more mast cells, eosinophils, IgE
The infants immune system needs stimuli to develop regulatory T cells which mediate tolerance and dampen immune response
More recent work of HH reveals that…
Benefit of early infection depends on the type and timing of infection
more antibiotics now given in early life which affects colonisation of bowel by good bacteria
What are some points of evidence for the HH?
Allergic and autoimmune disorders less common in developing countries
migration from developing to developed world leads to greater incidence of these conditions
Early life exposure of mice to infections - a reduced incidence of autoimmune disease
What are some points of evidence against the HH?
microbial diversity may be more important than the numbfer of infections
Asthm rates are declining in some developed nations while food allergy continues to rise
many other factors linked to an increase in asthma and allergy:
delayed intro of solids
air polution
household damp and airbourne moulds
family history
Most asthmatics are atpoic, but only some atopic children…
progress to asthma
Long term birth cohort studies show 3 things which add together to form the greatest risk of persistent asthma, what are they?
LRTI + aeroallergen sensitization + family history of asthma
Why does respiratory infections link to an altered tolerance?
Viral infection alters normal maturation and turnover of dendritic cells
Early respiratory infection may be a sign of predisposition to asthma, and not a cause
Th2 cytokines stimulate…
IgE production
more severe LRTIs (e.g RSV) more strongly linked to athsma than ..
uncomplicated URTIs
Some risk factors of asthma overlap with the HH - what are they?
Inactivity / too much time indoors
- too little Vit D (impaired immunity)
- Obesity
c-section delivery - slight increase in asthma (don’t get early colonization by mother’s flora)
Ciggy smoke exposure irritates airways
What are the public health messages for HH and asthma?
Dirt is good, to some extent…
not all micro-organisms are harmful, but need to avoid serious infections (vaccination decreases occurence of infections that can kill or have permanart consequences - whooping cough, measles are BAD)
What are the treatments for asthma exacerbations?
initial treatment - inhaled B2-agonists and steroids
moderate cases: antibiotics, nebulized b2-agonists, oral steroids
severe cases: i.v bronchodilators
most severe: ICU - intubation
80% of asthma exacerbations are caused by …
viruses - especially Rhinovirus
What is the trigger for interferon (IFN) produciton?
dsRNA - we don’t make it, must be from virus
true or False
IFN is part of the innate immune response
true
Why do asthmatics get worse and longer colds?
Both +/- asthma had similar basal ICAM-1 levels
but, asthmatic cells have higher Rhinovirus replicaiton 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
