Influenza

Question 1

Outline the basic pathogenesis of seasonal influenza

Answer 1

Droplets containing virus enter RT
Virus binds to sialic acid-containing receptors on non-cilicated respiratory epithelium
Virus replicates in epithelial cells of upper and lower RT but particularly in the large airways
Tissue damage and ensuing inflammatory response causes local and systemic symptoms
Pre-existing and developing immunity is sufficient to clear the virus in immunocompetent individuals

Question 2

How can influenza cause a secondary bacterial infection?

Answer 2

Viral replication can occur in ciliated epithelium later in the infection, predisposing to bacterial infection

Question 3

Describe the structure of the influenza virus

Answer 3

Enveloped with segmented -ive sense ssRNA genome

Question 4

How are types of influenza differentiated?

Answer 4

By antibodies to the internal antigens

Question 5

What types of influenza cause human influenza?

Answer 5

A, B (C is a minor pathogen)

Question 6

What is HA? What is its role?

Answer 6

Hemagglutinin, dominant surface gp on influenza

Binds to sialic acid-containing receptor

Question 7

What is NA?

Answer 7

Neuraminidase

Cuts sialic acid-containing receptors from the cell surface so that newly budded virus won’t bind back to the dying cell

Question 8

What is NS1? What is its role?

Answer 8

Non-structural protein produced by influenza following entry into the host cell
Has anti-IFN activity

Question 9

What is M2 and what is its significance?

Answer 9

Ion channel on surface of influenza virus

Target for anti-virals

Question 10

Describe the replication cycle of the influenza virus

Answer 10

Viral HA binds receptor
Virus taken into cell via receptor-mediated endocytosis
As the endosome becomes more acidic (due to the action of the M2 ion channel), HA changes conformation leading to fusion of the viral envelope with the endosomal membrane, forming a pore
The 8 ribonucleoproteins (RNPs) are released and go to the nucleus, where viral protein replication and mRNA synthesis occurs
Viral RNPs form in the cytoplasm; concurrently, viral protein is synthesised
Following glycosylation in the ER and golgi, HA and NA are expressed on the host cell surface
Virion is assembled and buds out of the cell, acquiring their surface gps and envelope
Viral NA cuts sialic acid receptors from cell surface to prevent newly released virus binding back
Action of tryptase Clara reveals a hydrophobic fusion peptide on HA, allowing further infection

Question 11

How are type A influenza viruses named?

Answer 11

After the HA and NA subtypes they express

Question 12

Why is influenza confined to the RT despite the ubiquitous distribution of the sialic acid-containing receptor?

Answer 12

Action of tryptase Clara (secreted by Clara cells) is required for fusion and endosome escape, so virus is confined to the RT

Question 13

Why are our own antibodies ineffective against influenza?

Answer 13

Antigenic drift of the virus

Question 14

What is antigenic drift?

Answer 14

Process whereby viruses that acquire mutations (through errors of replication of the viral RNA-dependent RNA polymerase) which are advantageous for infection are selected for

Question 15

What are the common sites for mutation in antigenic drift?

Answer 15

In the binding sites for antibody on HA and NA

Question 16

What are the targets for the influenza vaccine?

Answer 16

HA

NA

Question 17

What is contained in the influenza vaccine?

Answer 17

Inactivated trivalent vaccine containing the 3 most recent strains of influenza A H1N1 and H3N2 subtypes, and influenza B

Question 18

For what people is the influenza vaccine recommended?

Answer 18

>65 y.o.
Chronic lung, heart or kidney disease
Diabetes
Cancer
Immunosuppression
Health and childcare workers

Question 19

What is 1 contraindication for the influenza vaccine?

Answer 19

Egg allergy (virus is grown in eggs)

Question 20

What kind of a response does the influenza vaccine produce? Why?

Answer 20

Induces antibody but not cytotoxic T cell responses because it is an inactivated vaccine

Question 21

What are the targets of antiviral drugs to treat influenza? How do they work?

Answer 21

Ion channel blockers: inhibit function of M2 ion channel, preventing endosome escape of RNPs
NA inhibitors: block efficient release

Question 22

Amantadine

Answer 22

Influenza antiviral

Blocks M2 ion channel

Question 23

Limitations of adamantanes

Answer 23

Not active against type B
Drug resistance (not used widely in the community)

Question 24

Rimantadine

Answer 24

Influenza antiviral

Blocks M2 ion channel

Question 25

Relenza/zanamivir

Answer 25

Influenza antiviral

Blocks NA

Question 26

Tamiflu/oseltamivir

Answer 26

Influenza antiviral

Blocks NA

Question 27

What is antigenic shift in terms of influenza?

Answer 27

Refers to sudden appearance of an influenza A virus with a new HA (and sometimes NA), derived from birds
Causes pandemic

Question 28

What is reassortment and how does it produce new human subtypes of virus?

Answer 28

A common viral host for human and avian influenza is infected with a strain of both
Mixing of genomic material occurs which results in the production of a virus with avian HA and NA but human internal genes specific for SA a2-6

Question 29

What part of the sialic acid receptor does human influenza virus bind to? What part does avian influenza bind to?

Answer 29

Human: SA a2-6 Galactose
Avian: SA a2-3 Galactose

Question 30

What is special about avian H5N1 influenza?

Answer 30

Doesn’t require tryptase Clara for infective action and so can infect systemically (makes it highly lethal)