Respiratory Virology Flashcards
What are the symptoms of seasonal influenza?
Typical Influenza:
Fever/chills
Cough
Headach
Muscle ache
Fatigue
Loss of appetite
(Normal CXR)
Acute infection:
lasting 7 days or longer
Weakness and cough may last for several weeks
What groups are at-risk of severe complications and death from influenza virus?
- The young
- The elderly
- Those with underlying chronic heart, lung, renal and metabolic conditions
How is influenza virus spread?
Droplet infection from coughing and sneezing (but don’t go very far)
What is the incubation period for influenza virus?
1-5 days
How long are influenza sufferers infectious for?
5-6 days
What is the total annual cost of influenza on the Australian healthcare system?
$600 million
How many deaths are attributed to Influenza worldwide each year?
250000-500000 deaths
How does the influenza virus infect the respiratory tract?
It binds to the sialic acid-containing receptors on non-ciliated respiratory epithelium in an alpha2-6 linkage to galactose in humans
Although these receptors are on other cells throughout the body, influenza virus remains localised to the respiratory tract
Where does influenza virus replicate?
In the epithelial cells of the upper and lower respiratory tract, but especially in the large airways
Later in the infection, viral replication may occur in the ciliated epithelium of the trachea and bronchi - this brings about the possibility of secondary bacterial infection (by H.influenzae, S.aureus, S.pneumoniae); contributes to death from bacterial pneumonia (especially in the elderly)
Viral replication rarely occurs within the lung parenchyma, resulting in primary viral pneumonia
What family does influenza virus belong to?
Orthomyxoviridae
What are the characteristic features of the influenza viruses?
It is an enveloped virus
Has a segmented (-) sense ssRNA genome - so it must carry its own RNA polymerase
How many types of influenza virus are there?
3 types - A, B and C They show no immunological cross-reactivity Main ones that cause human disease are types A and B Only type A influenza viruses infect other species (therein lies the danger to humans becoming infected from other animal species)
What is the NS1 (non-structural protein) associated with the influenza A and B virion?
It is a non-structural protein that has anti-interferon activity, which is important because RNA viruses are susceptible to the effects of interferons
What is the role of Haemagglutinin (HA)?
“The gripper”
- Binds to the surface receptor (sialic acid linked to galactose) on the respiratory epithelial cells, facilitating adherence, after which receptor-mediated endocytosis may occur
What is the role of Neuraminidase (NA)?
“The snipper”
- Cuts sialic acid receptors from the cell surface so that newly budded virus won’t bind back to the dying cell
How do influenza type A virus subtypes differ?
They have different forms of HA and NA
There are 16 different HA subtypes (H1-H16) and 9 different NA subtypes (N1-N9)
Antibodies are only specific to a single HA or NA subtype
What was the ancestral host of influenza type A virus?
Aquatic birds
All of the different subtypes of HA and NA are found on viruses endemic in avian species
What are some significant influenza type A subtypes that are currently circulating in humans?
H1N1 and H3N2
What does newly formed virus require to become infectious?
The action of tryptase Clara (produced by Clara cells in the respiratory tract) causes cleavage of HA to reveal a hydrophobic fusion peptide, necessary for the conformational change that allows viral infection
What are the two main adaptive immune responses to influenza virus infection?
CD8+ cytotoxic T cells:
- Kill the virus-infected cells
- Important in recovery
- Recognised peptides derive from internal antigens of the virus, so they are broadly cross-reactive between type A subtypes, but not between types A and B
- Not long-lived immunity, but boosted by repeated exposure
Antibody:
- Developing AB to HA and NA speeds clearance of the virus
- Acts by inhibiting attachment (or release) of the virus)
- Also antibody+complement complexing allows lysis of cells, and promotes phagocytosis Pre-existing Ab will protect against infection by neutralising input virus
What is antigenic drift?
The selection of viruses with mutations in the sites on HA or NA where neutralising antibodies bind, rendering them ineffective
This leads to the creation of new strains within a subtype
Once all 5 antigenic sites surrounding the receptor-binding pocket have mutated (such that they are no longer recognised by pre-existing antibodies), an epidemic virus strain will result
What are the targets of vaccine-induced immunity to influenza?
Antibodies to HA (to block viral attachment) and NA (to block efficient infectious virion release)
What is the influenza vaccine?
An inactivated trivalent vaccine containing 3 different viruses representing the most recent strains of:
- Influenza A H1N1
- Influenza A H3N2
- Influenza B
There may now be some quadrivalent vaccines with two subtypes of Influenza type B
It is grown in (fertilised chicken) eggs, and purified from allantoic fluid - therefore unsuitable for people with egg allergies. They are chemically inactivated and disrupted with detergent before administration (to ensure that infection is not possible upon vaccination)
How is influenza vaccine administered and to whom?
It is injected intramuscularly
Recommended for those at risk from complications of influenza, including:
- People over 65 years of age
- People with chronic lung, heart or kidney disease
- People with diabetes or cancer
- People with immunosuppression
Also recommended for health workers, who may transmit the virus to those at risk
What are the targets of antiviral drugs?
- Ion channel blockers (inhibiting M2, which prevents endosomal escape of RNPs)
- NA inhibitors (blocking efficient infectious vision release)
What are the adamantanes?
Amantadine and Rimantadine are two different adamantanes
- Block the M2 ion channel, inhibiting the uncoating of influenza A virus in the endosome during entry, preventing infection (not active against type B)
- Given daily (orally)
- Used for treatment in children and for prophylaxis in nursing homes to prevent widespread outbreaks
- Not widely used because drug-resistant mutants of influenza virus readily arise
What are the NA blockers?
Relenza (Zanamavir) and Tamiflu (Oseltamivir)
They are active against influenza A and B, reducing the duration and severity of disease, but they are only effective if given within 2 days of developing symptoms.
Given twice daily
Relenza: administered by inhalation
Tamiflu: administered orally (as a prodrug) - some resistance has developed
What is antigenic shift?
The sudden appearance of an influenza A virus with a new HA (and sometimes NA) within the human population, usually derived from birds
The complete lack of protective immunity leads to a rapid global spread, high morbidity and mortality - giving rise to a pandemic
Why are pandemics rare?
Because the human influenza A virus receptor sees SA alpha-2-6 Gal and the avian virus receptor sees SA alpha-2-3 Gal
A single amino acid change in the receptor binding pocket of HA can lead to a change in receptor-binding specificity
How are new human influenza A subtypes created?
By reassortment (the swapping of gene segments upon co-infection of a single cell)
This may occur in pigs, because they have both the human and avian virus receptors in their respiratory tract
How does influenza virus escape the endosome?
The endosomal proton pumps that normally acidify the endosome cause HA and NA to be exposed to an acidic environment. When HA is exposed to acid, a conformational change is induced that exposes a fusion region, which is necessary for mediating fusion of the viral envelope with the endosome for viral escape into the cell
However, the viral genome requires the activity of its own M2 ion channel that pumps H+ inside the viral envelope such that they contact the genome, to unlock it from the viral matrix and allow appropriate release into the cell upon envelope-endosomal fusion.
What can antigenic shift result from?
- Direct infection with avian virus (in 1918; followed by adaption via mutation)
- Genetic reassortment in 1957 and 1968
- Reintroduction of previous human strain in 1977
What were the characteristic features of the 1918-1919 influenza pandemic?
25-30% of the world’s population were clinically infected 20-50 million deaths worldwide
Deaths were unusually high in the 15-35yo age group
Rapid disease onset/progression (often less than 5 days)
Associated with pulmonary oedema, haemorrhage and cyanosis
What characterised the recent H1N1 outbreak (“Swine flu”, 2009)?
Respiratory symptoms
Person-to-person spread
Not highly lethal to humans (compared to H5N1 or previous H1N1 - most deaths occurred in people with underlying conditions)
Deaths in younger people (perhaps some immunity in older people induced by earlier seasonal H1N1)
Greater ability to replicate in the lungs (than seasonal influenza), so some young otherwise-healthy adults developed viral pneumonia
Most susceptible groups:
- Pregnant women
- Obese individuals
- Indigenous populations
Susceptible to NA-inhibitors
What is unique about the most recent avian H5N1 influenza virus (“bird flu”)?
It is known as a highly pathogenic avian influenza (HPAI), because it can infect systemically due to a different cleavage site that can be cut by an enzyme found in all cells (not just in the respiratory tract and intestinal organs). This gives it the potential to spread systemically to other tissues (including the brain), and it also makes it highly lethal. Fortunately, cases appear only to be infected directly from birds
