Influenza

What are the features of the influenza virus (genetic material etc) (3)?

• 8 negative sense ssRNA segments

• 10 genes

• enveloped

What is influenza type A associated with (2)?

• seasonal epidemics

• sporadic, potentially devastating pandemics

How many species of influenza are there?

4 - A, B, C and D

What is influenza type B associated with?

seasonal epidemics

What is influenza type C associated with?

childhood cold

What is the main reservoir of influenza A?

birds / avian

What is required for the replication of influenza A and why (2)?

• viral RNA-dependent RNA polymerase

• genome is negative sense ssRNA - opposite polarity to mRNA so cannot be transcribed using normal transcription machinery

How is Influenza A replicated (2)?

• 8 segments - independently transcribed, replicated and packaged

• viral RNA dependent RNA polymerase required

What are the 2 main glycoproteins found on the surface of influenza A?

• HA - haemagglutinin

• NA - neuraminidase

What is the role of the HA (haemagglutinin) glycoprotein on Influenza A (2)?

• binds sialic acid to mediate viral entry

• 18 subtypes (2 only in bats)

What is the role of the NA (neuraminidase) glycoprotein on Influenza A (2)?

• removes sialic acid to allow viral exit

• 9 subtypes

What specifies the antigenic reactivity of influenza viruses?

HA and NA glycoproteins

What is the appearance of influenza A infection in healthy adult humans (2)?

• acute infection, resolves in 2 weeks

• long lasting neutralising antibody response

How does influenza A persistently infect healthy adult humans despite each infection raising a long lasting antibody response (4)?

• antigenic drift

• viral RNA dep RNA pol is highly error prone (rate of 1×10⁴)

• generates sequence variants in HA and NA

• functional antigenic escape mutants have a selective advantage

Why does Influenza A require constant surveillance and vaccine updates?

antigenic drift - rapidly develops new strains

What is included in the standard human Influenza vaccine (2)?

• 2 x A strains (H3N2, H1N1)

• 1 x B strain (Vic)

Why does the influenza A vaccine now only contain 3 strains when it used to contain 4?

the slowest mutating B strain went extinct during Covid

How is Influenza A similar to other zoonotic pathogens?

experiences significant species barriers

Why does Influenza A struggle to overcome the species barrier (4)?

• avian Influenza A does not generally infect mammals well

• viral genetics required for optimal replication differ between hosts

• all core genes contribute to host range (HA > PB2 > other genes)

• adaptation is a multistep process - intermediates may be less fit

Which Influenza A genes contribute to host specificity (2)?

• 10 core viral proteins - all contribute to host range

• generally HA > PB2 > other genes

How does HA (haemagglutinin) help establish the host range of influenza A (2)?

• different sialic acid requires different HA

• binds alpha2-6 sialic acid in mammals and alpha2-3 in avians

What does HA (haemagglutinin) bind in mammals to allow cell entry?

alpha2-6 sialic acid

What does HA (haemagglutinin) bind in avians to allow cell entry?

alpha2-3 sialic acid

Which sialic acid variants are found in humans and why is this important for Influenza infection (3)?

• mainly 2,6 sialic acid

• some 2,3 sialic acid but mainly found deep in lungs

• Influenza with HA specific for 2,3 would have to get deep into lungs to infect a human

How does PB2 (polymerase subunit) help establish the host range of influenza A (2)?

• binds ANP32 to replicate genome

• different PB2 variants needed for ANP32 in different species

How can PB2 be used to risk assess different Influenza A strains (3)?

• can reasonably predict what ANP32 variant PB2 will bind based on sequence

• if have K at position 627 - likely to work in human cells

• if have E at position 627 - unlikely to work in human cells

What is the role of the PB2 (polymerase subunit) in Influenza A?

interacts with host cell ANP32 protein to replicate genome (not make mRNA, replicate the genome itself)

What is reassortment?

specialised form of recombination due to having 8 separate RNA segments

How does Influenza reassortment work (3)?

• have 8 separate RNA segments

• 2 different Influenza species / strains infect same host

• exchange some RNA segments = new hybrid virus

What could be a potentially very problematic Influenza reassortment in terms of human infections (3)?

• hybrid virus with new NA and HA from avian virus

• retained other human segments

• would have no resistance in population to new NA and HA

How does reassortment of Influenza help the virus to overcome the species barrier (2)?

• reassortment ‘jumps’ the fitness barrier for adaptation

• no / fewer less fit intermediates compared to random mutations

What are some examples of past Influenza pandemics caused by reassortment (3)?

• 1918 - H1N1 Spanish flu (from avian influenza A pool)

• 1957 - H2N2 Asian flu (new NA and HA)

• 1968 - H3N2 Hong Kong flu (new HA)

Where does reassortment / adaptation of Influenza A often take place and why (2)?

• pigs - biochemically intermediate between avians and humans

• have abundant sialic acid alpha2.6 AND alpha2,3

What 2 recent Influenza A strains have been pandemic scares?

• H5N1 1997, 2003 onwards and again 2020 to now

• H7N9 2013-2017

What was the H7N9 pandemic scare and why did it not become a pandemic (3)?

• China 2013-2017

• 1300 cases in 5 waves with 20% mortality rate

• China introduced mandatory chicken vaccination

What was the H5N1 pandemic scare and why is it still a concern now (3)?

• Hong Kong 1997 = 18 cases, 33% fatality but no person-to-person

• 1997-2015 = 900 cases, 50% fatality

• now established in US dairy cattle (mammalian jump!)

Why is H5N1 in US dairy cattle a concern (4)?

• has made jump from avian to mammalian hosts

• patchy surveillance and control mechanisms

• infects cow mammary glands → difficult to clean milking equipment

• lots of human contact

What are 3 ways of trying to prevent future influenza A pandemics occurring (in terms of preventing new strains arising)?

• aim to reduce probability of reassortment and adaptation:

  • remove sources of zoonotic virus (slaughter, vaccines, wet markets)

  • prevent dual infection of exposed humans (vaccines & antivirals)

What are 3 ways of trying to prevent future influenza A pandemics occurring (in terms of preparedness)?

• surveillance

• vaccines prepared in advance (seedstocks)

• adequate antiviral supplies (e.g. tamiflu)

What is antigenic shift in Influenza A (3)?

• sudden, major genetic change resulting in a new subtype

• commonly caused by genetic reassortment

• can result in pandemics

What is antigenic drift in Influenza A (2)?

• gradual process of small genetic changes (mutations)

• can cause seasonal flu outbreaks as virus changes enough to overcome previous immunity

What is a pandemic?

global spread of a disease across multiple countries / continents (e.g. covid)

What is an epidemic?

affects more people than expected in a specific area (NOT global) (e.g. Ebola)

What does it mean if a disease is endemic?

constantly present in a population or region (e.g. malaria, common cold)