L19. Acute Infection: Influenza Flashcards
What are the two types of influenza infection?
Seasonal
Pandemic
What are the typical symptoms of influenza?
Fever/chills Cough Headache Muscle aches Fatigue Loss of appetite
Describe the infection course (timing) of influenza
it is an acute infection INCUBATION: 1-5 days INFECTIOUS for 5-6 days Lasts about 7 days or longer NO persistence of the virus (weakness and cough may last for several weeks)
Who are the at-risk groups for severe infections?
Young
Elderly
Chronically ill (heart, lung, renal, metabolic)
Despite being a largely subclinical disease, why is influenza considered an important infection?
Because it has a very large economical burden
Because the worldwide mortality rate of influenza per year is very large (250,000 to 500,000 per year)
How is the influenza virus spread?
By droplet inhalation spread by coughing and sneezing and thus enter and infect the respiratory tract.
To what does the virus bind on the cell surface in the humans? What is important about this receptor?
The exact receptor is unknown
On non-ciliated respiratory epithelial cells
We know the virus binds to the SIALIC ACID which is S2alpha-6 linked to galactose
It is important because it is only expressed in the RT (localised infection)
What are the local symptoms of influenza infection? What causes them?
Caused by both the tissue damage by the virus and the subsequent host inflammatory response.
Fever (IL-1): cytokines and interferon
Malaise, head and muscle aches: IFN
What is meant by the synergistic interaction of influenza with bacterial populations?
Bacteria (H influenza, S aureus, S pneumonia) can take opportunity of the damaged cilia and RT environment and cause disease - secondary bacterial infection when they normally wouldn’t have
What family does the influenza virus belong to?
Orthomyxoviridae family
Describe the influenza virus structure
Enveloped
negative sense ssRNA with a segmented genome (8RNPs)
What are the three types of influenza why are they different?
Types A, B and C have no immunological cross reactivity (serologically different)
They cause the production of different antibodies to internal antigens
Which types of influenza virus are important to human disease?
Types A and B
Type A in particular is able to cross species barriers
Describe the influenza virus ribonucleoprotein (RNP) of Type A influenza
Has 8 gene segments (RNPs) of RNA wound in a helical structure protected by a capsid protein.
It has 3 RNA polymerase subunits
What the the most important proteins expressed on the viral surface?
- HA - Haemoagglutinin
- NA - Neuraminidase
- M2 - an ion channel for H+
- NS1 - Nonstructural protein 1
What is the purpose of the surface protein Non-structural protein 1?
It counteracts any interferon activity: protects the virus from the antiviral environment normally set up by interferon.
Thus it is anti-interferon
Which of the surface proteins interact with the sialic acid-containing receptors on human cells?
Both HA and NA interact and bind with the receptor (both have binding sites)
Describe the differences between the structure and roles of HA vs. NA
HA: is a trimer with 3 binding regions
It ATTACHES to the cell and this allows entry into the cell
NA: is a tetramer with 4 binding regions (mushroom shaped cell)
It also binds to sialic acid but it cuts it off the host cell
How do the different subtypes of influenza arise?
Different subtypes of influenza A share the same internal proteins (matrix, polymerase etc) but they have different expression of both the HA and NA proteins and hence have different antigenicity.
16 types of HA and 9 types of NA
Who are the original/ancestral hosts of the influenza A virus?
Aquatic birds
What are the three main influenza A subtypes that have circulated in humans in the recent decades?
H1N1
H2N2
H3N2
Currently only H1N1 and H3N2 are circulating
Describe the viral replication steps of influenza
- Viral HA binds to sialic acid linked to galactose receptor and it enters the cell by endosome fusion
- pH change occurs and the endosome membrane fuses with the viral envelope
- RNPs escape the cell to the nucleus
4, Viral RNA replication and mRNA protein synthesis - Protein modification and synthesis through the golgi and Er for HA and NA
- Virus buds out of the cell
- NA binds back to sialic acid and cleaves it off the cell
- Tryptase enzyme cleaves the virus HA proteins at a single site
- Virus goes to infect another cell
Why does NA cleave the sialic acid off the host cell?
To stop inefficient reentry of the viral particles into the dying cell
Why does tryptase clara enzyme cleave the viral HA?
Cleaves at a specific amino acid site to expose a hydrophobic fusion peptide that is important for the molecule to undergo membrane fusion and endosomal escape in the next cycle,
Describe the CD8 response to influenza infection
Memory CD8 T cells can kill the virus-infected cells as they recognise INTERNAL ANTIGENS of the virus due to the broad cross reactivity between the Type A subtypes.
This is not long lived and can be boosted with repeated exposure
Describe the antibody response to influenza infection
Inhibit the attachment or release of the virus (against HA or NA) and can kill by complement or can opsonise for phagocytosis.
Pre-existing antibodies don’t protect against new virus subtype infection
Why are antibodies ineffective in preventing recurrent influenza infections?
ANTIGENIC DRIFT which creates new strains within the subtype.
Mutations due to errors in polymerase (no proof reading) leads to accumulation of mutations called DRIFT
If the changes occur in the antibody neutralising regions (HA or NA) then these are selected for and this is called ANTIGENIC SHIFT
How many binding epitopes are in HA?
5 different antigenic sites surrounding the binding region and accumulate mutation here.
What causes an epidemic?
When there are mutations in all 5 antigenic sites and thus the vast majority of the population have antibodies that are not at all effective at binding to the HA and neutralising it.
What are the targets of vaccine-induced immunity for influenza?
HA blocking attachment
NA blocking release
Describe the influenza vaccine
An INACTIVATED trivalent vaccine with 3 influenza viruses representing the most recent strains of influenaa A and B
Viruses is grown in eggs and purified from allantoic fluid. The virus is then chemically inactivated and detergent disrupted.
Who is the influenza vaccine given to and how?
Intramuscularly administered to at risk people (children, elderly, chronically ill and health workers at risk of passing on the virus to at risk people)
What are the targets for antiviral drugs in influenza?
- NA inhibitors
2. Ion channel blockers
Describe the NA inhibitors (examples and mechanism of action)
Relenza (Zanamivir) - inhaled and Tamiflu (Oseltamivir) - oral (prodrug)
Active against both A and B
reduces duration and severity of disease but is only fully effective within 2 days of developing symptoms
2x daily
Describe the M2 ion channel blockers (examples and mechanism of action)
ADAMANTANES: Amantadine and Rimantadine
Block the M2 ion channel and inhibit the uncoating of influenza A in the endosome (prevents pH change) and thus prevents infection.
Oral, daily
What is meant by designer drugs?
Small molecules (analogs of sialic acid) which bind irreversibly to the active site of NA and blocks its enzymatic activity and interferes with the release of new virus particles from the cell.
What is antigenic shift? What does it cause?
When there is a SUDDEN appearance of a new subtype influenza A virus of new HA (sometimes NA) in the human population
Causes pandemic = global spread due to a complete lack of protective immunity. (often with high morbidity and mortality)
Why are pandemics/antigenic shift rare?
Because humans have a S2α-6 sialic acid-containing receptor
While acquatic birds (the source of the new subtype) have S2α-3 sialic acid-containing receptors for the virus
Hence the virus doesn’t recognise any receptor on the human if it tried (without the very rare mutation to do so - even if the mutation occurred it would need to meet a human or die in the bird)
What is the major means of creating a new human subtype of influenza?
REASSORTMENT in a mixing vessel: the pig
The pig contains both the S2α-6 (human) and S2α-3 (bird) receptors and thus infection with a human and a bird specific virus (CO-INFECTION) can lead to ASSORTMENT of the viral segments when they infect the SAME CELL.
