Infectious Diseases Week 9

How many people contract influenza per year

25 to 50 million people contract influenza/year

Is influenza highly contagious

yes

when is influenza more common

during colder seasons

How is influenza transmitted

Through respiratory droplets

What is the incubation time for influenza

1-2 days from time of infection

What are the symptoms of influenza

Fever, headache, fatigue, muscle weakness and pain, sore throat, bronchitis, dry cough, sinus infection, exacerbation of asthma and obstructive pulmonary disease

What causes the majority of influenza-related deaths

Complications of the flu rather than the actual influenza virus

What secondary outcomes can occur with influenza

Bronchitis and pneumonia – especially in the elderly, young children, and immunocompromised

What type of virus is influenza

RNA virus

What is the genome size of influenza

~14 kb in size → 10 genes

How are influenza genes encoded

On separate (-) ssRNA segments

How many segments does Influenza A and B have

8

How many segments does Influenza C have

What proteins does the influenza genome encode

3 polymerase proteins (PB1, PB2, PA)

2 major surface glycoproteins: haemagglutinin (HA) and neuraminidase (NA)

3 structural proteins (NP, M1 and M2)

2 nonstructural proteins (NS1 and NS2)

How is the RNA packaged in influenza

RNA is packaged with nucleoprotein into a helical ribonucleoprotein form → three polymerase peptides for each RNA segment

Is influenza an enveloped virus and where does it derive its bilayer from

Yes – it derives its lipid bilayer from the plasma membrane of a host cel

What percentage of spikes are HA

80%

What is the function of HA

Attachment of the virus to a host cell

What percentage of spikes are NA

20%

What is the function of NA

Facilitates release of newly produced viral particles

What family does influenza belong to

Orthomyxoviridae

What are the three different genera/types of influenza viruses

Influenza A, Influenza B, Influenza C

what is the most important human pathogen

influenza A

how can influenza A be distinguished into

different subtypes e.g. H3N2

what does influenza infect

a wide variety of birds – waterfowl, shorebirds & gulls

humans

what is influenza A thought to be ancestors of

influenza strains currently circulating in swine, horses, and humans

characteristics of influenza B

only infects humans

characteristics of influenza C

Only infects humans. Generally non-symptomatic/mild respiratory infections

What is antigenic drift in influenza

New influenza viral variants emerge through mutations within the virus antibody-binding sites of haemagglutinin, neuraminidase, or both

Do antigenic drift mutations accumulate over time

yes

Which influenza types does antigenic drift occur in

all of them (A,B,C)

Does antigenic drift change the viral subtype

No – antigenic drift does not change viral subtype. E.g., H1N1 is still H1N1 but a mutated variant of it

Why do RNA viruses show a high degree of antigenic diversity

RNA polymerases of RNA viruses lack a proofreading mechanism → mutations accumulate causing minor changes in antigens

Why do influenza outbreaks occur annually

Because of influenza genome plasticity

What do accumulated changes over time alter/do in influenza(4 things)

i. The shape and electric charge of viral surface antigens – particularly on exposed distal surface and around RBS of HA

ii. Affect the antibody binding sites (i.e., epitopes)

iii. Allow escape from antibodies raised by prior infection or vaccination

iv. May result in poor detection in antibody-based assays (PCR improves this)

What is antigenic shift?

Occurs when one cell becomes simultaneously infected by two different strains of type A influenza

Which influenza type does antigenic shift occur in

Occurs only in influenza type A

Why does antigenic shift occur only in influenza A

The broad range of hosts susceptible to influenza A appears to increase the likelihood that this event will occur

What causes antigenic shift

Gene reassortment – exchanges of whole gene segments in HA or NA → results in a new subtype of the virus

What is the consequence of antigenic shift

Sudden change in antigenicity associated with pandemics

What is thought to be responsible for most antigenic shifts

Mixing of strains that can infect birds, pigs, and humans

How many major types of haemagglutinin are there

16 major types (H1-H16)

How many major types of neuraminidase are there

9 major types (N1-N9)

What is the major change in antigenic shift

Major change in influenza virus antigens due to gene reassortment

Is reassortment the same as genetic recombination

No – reassortment is not the same as genetic recombination

When does reassortment occur

When 2 viruses infect the same cells and the viral gene segments randomly mix/reshuffle giving rise to a new viral subtype

Why do pigs act as a mixing vessel

Pigs express both types of receptor for influenza viruses as birds and humans

how do influenza pandemics occur

periodically

Although 16 HA and 9 NA variants have been identified, how many combinations are responsible for human epidemics

Only three combinations: H1N1, H2N2, and H3N2

What characterises influenza pandemics

Rapid worldwide spread of virus. Contain a HA and sometimes an NA to which humans have no previous exposure

What do pandemics result in

High rates of morbidity and mortality; social disruption; economic loss

what was the 1918 spanish flu

H1N1 – exceptionally deadly global influenza with ~50M deaths

Many young people died just a few days after infection with virally induced haemorrhagic pulmonary oedema

What was the 1968 Hong Kong flu

H3N2 – low virulence/high transmissibility characteristics, <1M deaths

What was the 2009 swine flu

H1N1 – reassortment of 4 strains of influenza A virus subtype H1N1: one endemic in humans, one endemic in birds, two endemic in pigs

What is the goal regarding future influenza pandemics

Monitor animal viral subtypes and predict possible reassortment

What subtype is highly pathogenic avian influenza

H5N1

What is the case fatality rate of H5N1 in humans

~60%

Do current circulating H5N1 viruses have the ability for efficient and sustained transmission among humans

No – they lack this ability

What would happen if H5N1 acquired genetic changes for efficient transmissibility among humans

Another pandemic would likely occur

How long can influenza virus remain circulating after a pandemic

For many years/decades, before being replaced with a new virus

Since 1977, what strains appear to be co-circulating

H1N1 and H3N2

When is influenza said to be an epidemic

When the incidence of influenza-related illness rises above the seasonal baseline

When do winter outbreaks of influenza occur

In both northern and southern hemispheres

Can influenza be isolated year-round

Yes – influenza can usually be isolated from patients somewhere all year round

How many predominant types or subtypes of influenza usually circulate during a season

Usually one predominant type or subtype

What do avian viruses preferentially bind to

Avian viruses preferentially bind viral HA to sialic acid receptors with galactose linked via α2,3-glycosidic bonds

Where are α2,3-linked sialic acid receptors found

On intestinal epithelia in birds

What do human tracheal epithelial cells express

Sialic acid decorated receptors that have α2,6-glycosidic bonds

What accounts for host specificity of influenza viruses

Difference in receptor specificity

What does host specificity limit

Limits spread of bird viruses → humans.

If transmission occurs, it is usually poor and virus can't spread very well – highlighting the importance of adhesion and expression of specific receptors to allow infection

What does the NA protein do

Cleaves the sialic acceptor to release the new virion

What happens during normal viral replication

NA cleaves the sialic acid receptor, allowing release of new virions and spread

What happens without NA

The virus would remain attached to the sialic acid receptor and not spread

What sialic acid receptors do pigs express

Both α2,3-linked and α2,6-linked glycosidic bonds

What does this allow pigs to be infected by

Both bird and human influenza viruses

What role do pigs play in influenza

They act as a "mixing vessel" where genetic reassortment and selection of novel viruses may occur

When was the last swine flu pandemic

2009

What must occur for a pandemic to happen

A novel influenza virus must form

what does Genetic reassortment of viral RNA segments lead to

expression of new surface glycoprotein(s) (HA and/or NA).

The immune system has no existing immunity to the antigen

What must happen for reassortment to occur in pigs

Two viruses must infect the same cell in a pig

Why is this rare event possible

Because pigs express both human and bird sialic acid receptors

What does genetic reassortment cause

The random association of 8 different genetic segments

What determines if the new virus has pandemic potential

If the new virus can replicate and transmit from the pig to other hosts

what is The Host Immune Response with a contemporary strain of influenza

Limited virus replication and dissemination →

Activation of normal innate immune response →

Transient activation of α/β-interferons, proinflammatory cytokine and chemokine responses →

Few or mild clinical symptoms. Fatal pneumonia or death secondary to infection. <0.1% case fatality

what is The Host Immune Response with the 1918 pandemic strain

Wide dissemination. High and rapid replication →

Activation of overactive innate immune response →

Aberrant and persistent activation of proinflammatory cytokine and chemokine responses →

Severe clinical symptoms. Decreases in lung function. Acute respiratory distress syndrome. Severe tissue damage. Extensive oedema and haemorrhage. Fatal primary pneumonia. >2.5% case fatality

What do innate immune responses stimulate

IFN-I

What does the humoral immune response produce

Antibodies that recognise HA/NA

How do antibodies provide protection

By blocking viral binding to target cells and subsequent cell entry

When do antibody titres peak?

Within several days of infection

When do antibody titres decline

Over the following 6 months

why aren’t antibodies essential for protection

individuals without them still recover from infection

What is the main role of antibodies

To prevent re-infection with the same viral strain

What may cell-mediated immunity protect due to

Action of antigen-specific CD8+ T-cells

What happens to virus growth in primary, secondary, and tertiary infections

Primary: highest peak.

Secondary: lower peak, faster decline.

Tertiary: lowest peak, fastest decline

What happens to CD8+ CTL response in primary, secondary, and tertiary infections

Primary: slowest rise, lowest peak.

Secondary: faster rise, higher peak.

Tertiary: fastest rise, highest peak

What do vaccines allow for

Development of effective adaptive memory responses

What is the relationship between memory cells and viral load

Increased memory cells → decreased viral load

How is viral load measured

In logarithmic (log10) levels

what are examples of antiviral influenza medications

Amantadine and Rimantadine

Zanamavir and Oseltamivir