Influenza Viruses by James McSharry, PhD
Summary
TLDRIn this lecture, Professor James Macari discusses influenza viruses, focusing on their structure and replication process. He explains the difference between low and highly pathogenic strains, the current circulating strains like H5N2 and H5N8, and the 2014 outbreak's link to bird migration. Macari also covers antiviral treatments, including ion channel blockers and neuraminidase inhibitors, and the development of vaccines, highlighting the challenges of creating effective vaccines due to the virus's high mutation rate.
Takeaways
- ๐ฆ Influenza viruses are negative sense, enveloped RNA viruses that infect various species including birds and humans.
- ๐ Current circulating strains include H5N2 and H5N8, with geographical spread linked to bird migration.
- ๐ฌ The virus structure consists of two main surface proteins: Hemagglutinin (H) and Neuraminidase (N), which are crucial for viral attachment and release.
- ๐ฟ H5N1, which first appeared in China in 1997, has mutated into H5N2 and H5N8, causing significant issues in poultry worldwide.
- ๐ก The severity of influenza can range from mild to deadly, with highly pathogenic strains being more deadly due to their ability to infect various organs.
- ๐งฌ Influenza viruses are typed into A, B, and C based on the antigenic properties of their nucleoprotein and membrane proteins.
- ๐ Antiviral drugs like amantadine and rimantadine target ion channels of the virus, but resistance is a concern.
- ๐ The 2009 H1N1 pandemic virus spread globally causing a large number of infections, though not as severe as initially feared.
- ๐ Current vaccines include inactivated vaccines and live attenuated influenza virus vaccines, designed to induce antibodies against specific antigens.
- ๐ The need for annual flu vaccines arises from the constant mutation of the HA protein, necessitating updates to match circulating strains.
- ๐ฌ Research is ongoing to develop broadly reactive antibodies and vaccines that could provide protection against all influenza strains.
Q & A
What are influenza viruses?
-Influenza viruses are negative sense envelope RNA viruses that contain segmented genomes. They infect various hosts including waterfowl, birds, and occasionally spread to humans and other animals, causing diseases that can range from mild to severe or even deadly.
What are the current circulating influenza viruses?
-The current circulating influenza viruses mentioned in the script are H5N2 and H5N8.
How did the H5N1 virus spread globally?
-The H5N1 virus appeared in China in 1997 and spread throughout the world, mutating into H5N2 and H5N8, which are causing significant problems in poultry today.
What are the two lipoproteins on the exterior of the influenza virus?
-The two lipoproteins on the exterior of the influenza virus are the hemagglutinin (H), which is responsible for attaching the virus to cells, and the neuraminidase (N), which facilitates the release of new virus particles from infected cells.
What is the function of the matrix protein (M1) in the influenza virus?
-The matrix protein (M1) in the influenza virus is a major structural protein that lies beneath the viral envelope, providing structural support to the virus particle.
How many ribonucleoproteins are contained within the influenza virus?
-There are eight ribonucleoproteins contained within the influenza virus, each associated with a segment of the virus's negative-sense RNA genome.
What are the different types of influenza viruses and how are they classified?
-Influenza viruses are classified into types A, B, and C based on the antigenic properties of the nucleoprotein (NP) and the matrix proteins (M). Type A viruses are further subtyped based on the hemagglutinin (HA) and neuraminidase (NA) proteins, with 16 known HA subtypes and 9 known NA subtypes.
What is the significance of the cleavage of the hemagglutinin protein in the pathogenicity of avian influenza viruses?
-The cleavage of the hemagglutinin protein is significant in the pathogenicity of avian influenza viruses because it determines how easily the virus can spread within a host. Low pathogenic viruses are cleaved slowly by trypsin-like enzymes, limiting their spread to the respiratory and gastrointestinal tracts. In contrast, highly pathogenic viruses can be cleaved by numerous proteases throughout the body, leading to systemic infection and increased virulence.
What is the replication cycle of the influenza virus?
-The replication cycle of the influenza virus begins with attachment to host cell receptors, followed by internalization into the cell's cytoplasm. The viral RNA is then released into the nucleus where it is transcribed into mRNA and replicated. New viral components are assembled and the virus particles are released to infect other cells.
What are the two main classes of antiviral drugs mentioned for treating influenza?
-The two main classes of antiviral drugs mentioned for treating influenza are ion channel blockers (like amantadine and rimantadine) and neuraminidase inhibitors (like oseltamivir and zanamivir).
What is the purpose of the live attenuated influenza vaccine (LAIV) and how is it different from the inactivated vaccine?
-The live attenuated influenza vaccine (LAIV) contains weakened live viruses that are delivered intranasally, providing a mild form of the infection that stimulates an immune response without causing severe illness. It is different from the inactivated vaccine, which contains killed viruses and is administered intramuscularly, typically with a needle.
Why is a new influenza vaccine developed each year?
-A new influenza vaccine is developed each year because the hemagglutinin antigen of type A viruses mutates randomly, leading to different antigens annually. This requires the vaccine to be updated to match the circulating strains and provide effective protection.
Outlines
๐ฆ Influenza Virus Basics
The lecture by James Macari introduces influenza viruses as negative sense envelope RNA viruses with segmented genomes. These viruses commonly infect waterfowl and can occasionally spread to humans and other animals, causing diseases ranging from mild to deadly. The current circulating strains are H5N2 and H5N8. The lecture discusses a significant event in 2014 where closely related viruses were detected in Asia, Europe, and North America, possibly linked to bird migration. The structure of the virus is explained, highlighting the hemagglutinin (H) and neuraminidase (N) proteins on its exterior. The process of viral infection, including attachment to cells, entry, and replication, is outlined. Influenza viruses are typed based on the antigenic properties of the nucleic acid protein and membrane proteins, with Type A being the most significant for human infections.
๐ฌ Pathogenicity and Replication
This section delves into the pathogenicity of avian influenza viruses, explaining how low pathogenic strains are slowly cleaved by trypsin-like enzymes, limiting infection to the respiratory and gastrointestinal tracts. In contrast, highly pathogenic strains can be cleaved by numerous proteases, allowing for systemic infection and greater deadliness. The replication cycle of influenza viruses is detailed, starting with attachment to host cells, followed by internalization, replication in the nucleus, and eventual release of new virus particles. The role of antivirals in treating influenza is also discussed, including ion channel blockers like amantadine and rimantadine, and neuraminidase inhibitors such as oseltamivir (Tamiflu) and zanamivir, which prevent the release of new viruses from infected cells.
๐ Antiviral Treatments and Vaccines
The paragraph discusses various antiviral drugs used to treat influenza, including ion channel blockers and neuraminidase inhibitors. It also mentions experimental compounds like DAS181, which removes sialic acid from respiratory tract glycoproteins to control infection, and T-705, an RNA-dependent RNA polymerase inhibitor. The current state of influenza vaccines is explored, including inactivated vaccines and live attenuated vaccines. The vaccines aim to induce antibodies against the type-specific hemagglutinin antigen but face challenges such as the need for annual updates due to viral mutations and varying effectiveness. The development of broadly reacting antibodies and universal vaccines is an active area of research.
๐ก Vaccine Development and Challenges
This section discusses the evolution of influenza vaccine production, moving from traditional methods to recombinant technology that uses plasmids of viral genes to create new vaccines. The challenges of vaccine development are highlighted, including the need for annual updates due to mutations in the hemagglutinin antigen of Type A viruses. The paragraph also covers the discovery of broadly reacting antibodies that target the conserved central region of the hemagglutinin, which could potentially lead to the development of universal vaccines. The lecture concludes with a discussion on the importance of continued research in influenza vaccine development.
Mindmap
Keywords
๐กInfluenza
๐กNegative sense envelope RNA viruses
๐กSegmented genomes
๐กHemagglutinin (H)
๐กNeuraminate (N)
๐กAntigenic properties
๐กReplication cycle
๐กAntivirals
๐กVaccines
๐กBroadly reacting antibodies
๐กPandemic
Highlights
Influenza viruses are negative sense envelope RNA viruses with segmented genomes.
Influenza viruses infect a variety of hosts including waterfowl and can occasionally infect humans.
The current circulating influenza viruses are H5N2 and H5N8.
Influenza viruses can spread through bird migration, as seen in the 2014 outbreak.
H5N1 appeared in China in 1997 and has since mutated into other strains causing problems in poultry.
The structure of the influenza virus includes two lipoproteins, hemagglutinin (H) and neuraminidase (N).
The M1 protein is a matrix protein, and the M2 protein is an ion channel involved in virus release.
Influenza viruses contain eight ribonucleoproteins with negative stranded RNA.
Influenza viruses are typed based on the antigenic properties of the nucleoprotein and membrane proteins.
Influenza A viruses are further subtyped into different groups based on pathogenicity.
The HA protein must be cleaved for the virus to infect cells, which differs between low and high pathogenicity strains.
Influenza A viruses like seasonal H1N1 and H3N2 occur annually, with H3N2 being a major cause in recent years.
The 2009 H1N1 pandemic virus spread worldwide causing a large number of infections.
Antivirals for influenza include ion channel blockers and neuraminidase inhibitors.
Amantadine and rimantadine are ion channel blockers, but resistance develops quickly.
Neuraminidase inhibitors, such as oseltamivir and zanamivir, prevent virus release from cells.
Experimental compounds like DAS181 and T-705 are being investigated for influenza treatment.
Current influenza vaccines include inactivated vaccines and live attenuated vaccines.
Vaccines are designed to induce antibodies to the type-specific hemmagglutinin antigen.
Vaccine effectiveness can vary, with the 2015 vaccine being only 20-30% effective.
New vaccine technologies, such as recombinant plasmids, have improved vaccine safety and efficacy.
Broadly reacting antibodies have been identified and are being studied for universal vaccine development.
Transcripts
[Music]
this first lecture will be on influenza
viruses presented by James Macari
professor emeritus of a medical college
Albany New York influenza viruses are
negative sense envelope RNA viruses that
contains segmented genomes they infect
waterfowl birds ducks ease things like
that occasionally influenza viruses
spread from waterfowl or other animals
including people causing mild to very
serious and often deadly disease current
influenza viruses that are circulating
through the world right now are h5 n2
and h5n8 this this particular slide
shows what happened in 2014 and the Oh
most simultaneous detection of closely
related viruses in Asia Europe and North
America
so just linkage with a bird migration
via large rate region in Russia now back
in 1997 h5n1 appeared in in China and
that spread throughout the world
now those h5n1 has mutated to become the
h5 h5 n2 and h5 n H which are causing
major problems in poultry throughout the
world today influenza virus is this is a
model of influenza virus on the exterior
there are two lipoproteins the
hemagglutinin or H a which is the blue
knob
is this this DHA attaches the virus to
salic acid containing receptors on the
surface of the cell the n na is the norm
in today's this is a tetra mer this is
the orange colored glycoprotein on the
outside of the virus particle and this
protein actually functions as the virus
is released from the cell inside the
first one is the matrix protein the m1
protein this is one major proteins of
the virus particle coached to complete
inside of the lipid envelope of the
green proteins or the m2 protein is an
ion channel which is involved in
encoding the virus inside the cell as we
enter the virus particle the interior
you see there are eight
ribonucleoproteins
labeled PD - PD one PAH a and T na and
NS these ribonucleoproteins
contain negative stranded RNA and
multiple copies of the na protein the
nucleic acid protein the influenza
viruses are designated they are typed on
the base of the antigenic properties of
the nucleic acid protein and the
membrane proteins and they are type a B
and C a and B because these and people
see is a minor entity in terms of human
infection but it is involved in other
infections swine influenza viruses is
type a influenza viruses are sub
a the energetic properties of the H a
and M a proteins there are 16 H a and 9n
a swine influenza virus is type a
subtype h1n1 the avian influenza viruses
um into two different groupings in terms
of their pathogenicity the in order for
the virus to infect the cell the H a has
to be clean so and it's cleaved the
trypsin trypsin like segments in low
pathogenic avian influenza viruses the
protease level is just four amino acids
and it's very slowly cleaved or its
markets not completing Germans but the
cleavage occurs in the respiratory tract
and in the gut only or is the highly
pathogenic avian influenza virus is
susceptible to numerous proteases so
cleavage occurs footage of the HEA
occurs throughout the animal and virus
infection can occur throughout the
animal and that is why it is much more
deadly influenza virus influenza viruses
influenza A viruses like seasonal h1n1
and h3n2 viruses these occur every year
and particularly recently we have more
h1n1 this past season 19 - or 2015-2016
h3n2 was the major cause of disease 2009
a new influenza virus appeared and was
pandemic h1n1 and this virus spread
throughout the world and caused very
very large numbers of infections it
wasn't quite as big as bad as people
worried
about what people thought maybe similar
to the 1918 pandemic which killed
approximately 50 million people this
h1n1 probably killed a much much smaller
number of people there's also an
influenza B viruses those are the humans
now the avian influenza viruses h5n1 h5
n2 h5 n 8 8 7 n 7 and h9 and to
occasionally spread from verged people
human infection with these avian
influenza viruses occurs rarely but can
be deadly
what it does occur all avian influenza A
viruses separate potential was influenza
pandemics pandemic is a worldwide
epidemic this is a replication cycle for
influenza viruses the first step is
attachment the virus attaches to cyclic
acid containing glycoproteins and
glycolipids on the plasma membrane of a
susceptible cell next step is put the
virus to get taken into the cytoplasm
through placing coated pits this is in
the pit the pH of the medium inside the
the endosome is reduced to about 6 under
which circumstances they even gloat the
hemagglutinin undergoes a conformational
change which allows the viral envelope
to fuse with the endosomal membrane
releasing the ribonucleoprotein so for
each of the eight ribonucleoproteins in
the virus they will get released into
the cytoplasm
now these proteins have nuclear
localization signals on them so they are
transported to the nucleus where two
kinds of transcription occur one is to
make
messenger rnas and this is a rather
interesting way to make messenger RNAs
the tack the 5-prime cat of cellular
newly made messenger RNA is cleaved off
and that's used as a primer to make
messenger rna's for each of the eight or
ten proteins of the virus and those are
all made in in the in the nucleus in
addition the ribonucleoprotein is copied
into a positive sense and then back into
a negative sense which is used to make
progeny viruses these viruses accumulate
and are released into the cytoplasm the
messenger RNAs for the H a and the
neuraminidase
associate with ribosomes and roughened
mm particular where they become bike
oscillated and exported to the plasma
membrane the other messenger RNAs are
made into proteins and those proteins go
back into the nucleus to form new nucleo
capsid and in this way the virus
replicates itself and and many many many
viruses are made now the there are a
number of antivirals that are used for
to complete patients who are exactly
with influenza originally they were ion
channel blockers remember to go back to
the model for the virus and there were
those green ion channels amantadine and
Romancing are very similar compounds
and they block that ion channel show you
a picture shortly they are only good for
type a influenza virus and currently
they are not recommended because they
generate resistant viruses very quickly
in addition to the ion channel blockers
there are enormous inhibitors these have
come about in the last couple of years
one is awful County our carboxylate also
known as Tamiflu it's good for both type
A and type B viruses and banana beer or
Belen for lens ax
also good for type A and type B these
two inhibitors block the ability of
influenza viruses to remove the salad
gases from the virus and hence the virus
tends to stay inside the cell and
doesn't get released
now for the amantadine that has blocked
the ion channels again Anthony just
sticks into the channel and blocked it
prevents the ions from flowing and hence
the pH doesn't change in the zone and
the virus doesn't understand code for
the norman ace inhibitors they block the
ability of the millah days to clean off
the terminal ayala gasses on these
lipoproteins and that again prevents the
release of the virus from itself in
addition to those licensed antiviral
drugs there are a number of experimental
compounds of treatment of influenza one
is called - das 181 this compound
removes alig acid from services of
glycoproteins and glycolipids of
themselves at the upper respiratory
tract just enough to control the
infection for not so much to cause harm
another
newly developed method well is T 7:05
this inhibits the RNA dependent RNA
polymerase
there are several novel compounds under
investigation for the inhibition of
influenza daughter
so it's a very active area of research
and another active area of research is
combination chemotherapy where more than
one drug is used at the same time you
probably ones the amantadine is plus
norm in today's inhibitors something
like that and that's an active field for
research current influenza vaccination I
rolled have vaccines the current
influenza vaccines are an inactivated
vaccine containing type a seasonal and
pandemic h1n1 viruses and fight a
seasonal h3n2 virus and type the
influenza virus oh so this has three or
four different viruses that are
inactivated and put into a solution
which is injected intramuscularly we
also have what's called a pole adapted
live attenuated influenza virus vaccine
which contains the same four strains
viruses inactivated vaccine and it's
delivered intranasally so there's no
needles kid-friendly but it is kind of
expensive this is a slide of somebody
giving the live attenuated vaccine to a
patient current flu vaccines type a and
type D viruses are designed to induce
antibodies to the type specific DJ Huen
antigen like attachment virus to the
cell presenting infections when they
work currently on a good day you get
about eighty percent protection close to
the fine sometimes it doesn't work at
all the current - 2015 vaccine is only
20 to 30 percent effective as an example
now the way the vaccines are made this
is fairly new this is 2004 paper from
dr. Peter Polizzi and what they did in
the past
I think the first influenza vaccines
were dissolved in 1940s and they just
threw the virus today and activated it
and all the vaccines but you have all
kinds of problems with that with the
authority to use recombinant technology
what they've done now is to make
plasmids of each of the eight genes for
the virus the H a and the NA and the P D
1 PB 2 PA and PM and NS and those are
all those plasmids are put into a cell
to make a new virus which is a
combination of the backbone the only the
AJ and the na are specific for the
parent vaccine the backbone comes from a
photo Rico which is well tolerated in
people and once they started using this
vaccine all of the programs that
compared with vaccines in the past or
most of the problems have gone away
problems with current employees acting
type A viruses random mutations of the
hae lead to different AJ antigens
each year therefore need a new vaccine
each year it's very expensive to make
and also is kind of hit or miss when you
get it correct as I said in 2015 the
vaccine didn't match very well about 30
percent effective and a few years ago
they had a vaccine that didn't work at
all so that's a problem
type D virus's does not change much from
year to year so that's not a problem
now they had
found that there are broadly reacting
antibodies and people so they have
figured out ways to make vaccines from
that and and on this slide uses a slide
of the H a it's a trimer and the the red
is the globular head this is where
individual mutations occur every time
the virus replicates basically and this
is why you have to make a new vaccine
each year because those antibodies are
directed against the head of the virus
now recently it's been discovered that
broadly reacting antibodies are also
generated in people over time and
they're directed toward the central
region of the evil group and a number of
these broadly acting antibodies have
been analyzed and and they are now being
studied and to be used as at the vaccine
which will work against all of the
influenza viruses all these in Taipei
and to inspire
[Music]
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