cc
hear me? >> All right, can everybody
for coming and welcome. I'd like to start just by
introducing myself and letting
I'm a Wisconsin native. you all Born and raised.e from.
I grew up in a small town in northwestern Wisconsin
called Balsam Lake. Graduated from Unity High School
there in the year 2000, and then went on to undergraduate
at the University of Wisconsin- Stevens Point, where I studied
biology and chemistry.
I've been here at the University Then for the last three years,
in the cell and molecular biology training program.
And I've been actively studying avian influenza viruses.
So my talk today will focus on human infection by these
avian viruses.
Al Bateman, my partner in crime Andwill be talking aboutthat
swine influenza after I've finished.
You guys will kind of get two sides of the story
of influenza today. ( inaudible )
The lab is located actually on the University of Wisconsin
campus. And yes, that's another thing
I want to note. If you guys have questions at
anytime throughout the talk,
So my first slide here feel free to just ask.
a sampling of all the known is different pathogens,you
as we like to call them.
with calling them germs, or bugs You're probably more familiar
within humans. that are able to cause disease
are probably the most common Inarguably, bacteria and viruses
And I'm sure all of you can name pathogens in humans.
from each of these groups. at least one or two members
and viruses, we also know But of fungal pathogens.ria
For example, there are many different Candida species
that are able to cause
We also know of histoplasmosis, which is a fungal infection of
the lungs and respiratory tract.
human pathogen. And they're far more prevalent
in the developing world than
But in the United States, we still do suffer from several
different round worm infections every year.
Protists are known
These involve, or include rather, the commonly known
giardia and cryptosporidium species, which are able to
induce very severe
And finally, perhaps one of gthe most interesting and.
yet perplexing pathogens that have come to human attention
over the last 20 years
Prions are really nothing more are what we call prions.
are able to replicate themselves than just proteins that
to organism, causing and transmit from organism
And we as scientists, still creally don't fully understande.
how prions work.
they include chronic wasting But I'm sure as all of you know,
in Wisconsin disease, which we have here
as well as the human counterpart in our deer population,
and mad cow disease. the Creutzfeldt-Jakob disease,
which one of these pathogens So just to survey the audience,
And if you've been paying hclose attention so far,a?
you already know the answer to that.
Anybody?
The virus, of course. So influenza is indeed a virus.
And viruses are probably
out there. one of the most simple pathogens
than a protein coat Thwith some nucleic acid,re
either DNA or RNA, inside.
classified as truly living And viruses aren't really even
some of the most devastating and organisms, yet they can cause
world's most complex organisms. deSo we ask, how is it thatthe
influenza viruses can make us sick?
Well, we know that flu
that means it can be transmitted is a respiratory pathogen, so
How this works, is the infected throindividual will coughoute.
or sneeze up infectious flu particles, aerosolizing them
in the immediate
If you're close enough, you can breathe in these infectious
particles which will make their way down to your lungs,
which is the primary site of influenza infection.
The lung provides the optimal environment for the virus
to replicate itself producing more virus.
Here we see an artistic representation of what happens
at the cellular level down deep in your lungs during
influenza virus replication.
flu virus particles will So in your lungs, individual
of your cells, actually comgain entry to your cells.face
And at this point,
the cellular processes, treorienting them so that yourr
cells are driven to become
factories, producing nothing more than viral
that go on to infect progeny virus particles
This continues to happen, and the viral replication process
actually ends up
This, in part, is one of the killing your lung cells.
when you get a flu infection. rOnce enough virus hasck
accumulated within your lungs.
or sneezing up the virus you will end up coughing
to the next person. This in essence is how
the human influenza virus perpetuates itself
in the human population.
of flu virus replication We can actually see evidence
highly-powered microscopes. This is an image taken with what
we call an electron microscope. And what we see, is here's
the edge of the infected cell.
tons and tons of infectious progeny flu virus particles.
So when I say that your cells become virus factories, I mean
it in a very literal sense. So how many of you
have had the flu before?
almost all of you. Okay, pretty much
it, but you're not too sure? Are any of you think you've had
That's because the symptoms No, associated with fluure.
are pretty bad. They're bad enough
that if you've had it once, you're going to remember it
for the rest of your life.
a high spiking fever, which is These symptoms include
of flu. usuA fever anywhere fromptom
100 to 104 degrees Fahrenheit.
a loss of appetite, Herespiratory secretionsa,
and muscle ache,
How about the stomach flu? a dry cough, and sore throat.
the stomach flu before? Well, that's funny, because
there's actually no such thing
The stomach flu was a general term that kind of arose
to describe gastrointestinal
associate with influenza virus problems that people came to
In fact, one of the problems infections.
misdiagnosed as many other with flu, is it's often
many other bacterial and conditions, because there are
what we call flu like symptoms. vHowever, you should neverc
experience gastroenterologic
unless you are a duck symptoms or a goose.infection
Avian species can get the flu actually, except they present it
as a gastrointestinal disease,
that gets flu presents it as a respiratory disease.l
If you think you have the flu,
the best thing you can do butis go to your doctor,ure,
get tested, get on
For most people, anti-virals, if necessary.
It last roughly one to two weeks, usually shorter
than that, and then it will resolve itself.
However, there are certain
at high risk for contracting groups of people who are
from influenza. And so this leads us to ask,
who can get the flu.
that everybody can get the flu. In fact, even your pet dog
or cat can get the flu. And I'll talk a little bit later
about how that happens. But in the United States,
every year, roughly five to 20% of our population is affected
one way or another
And these infections cause by influenza virus infections.
and roughly 36,000 deaths about 200every year.alizations
Now, these hospitalizations and deaths occur mainly
in high risk groups.
as the very young and very old, immuno-compromised individuals
such as HIV patients, pregnant women
or healthcare workers who will be in constant contact
with people who may be ill
Additionally, agricultural with the flu.
in constant contact with animals workers, especially those
poultry or swine workers, who are at increased riskch as
for getting influenza.
these people can do to prevent So the very best thing that
the flu every year is to get themselves from getting
In fact, the best thing you and I can do to prevent ourselves
from getting the flu
Now I'm sure many of you is to get our flu vaccine.
thoughts and feelings aassociated with this imagee
shown up on the screen. But how many of you got
your flu vaccine this year? Okay, good pretty much
everybody.
that you got your flu vaccine And how mathis year?are happy
Well, I'm glad to hear that,
probably know that the flu because even though most of you
efficacious this year as it should have been, it's still
a very good idea to get it. And I'll tell you why
in a moment.
Anyone know why we have to get But first one more question.
It's kind of a pain. the flu vaccine every year?
( inaudible ) >> Yes, that's exactly right.
The influenza virus is constantly changing.
And every year, new strains of influenza emerge that
are different from the strains
last year. you were vaccinated against
vaccine last year, doesn't mean you're going to the protected
from the circulating strains
this year. that are in the human population
is a seasonal disease. We all know that influenza
around the peak months The virus visits us every year
What I'm showing on the screen of December through March.
rate for the last four flu here is the influenza incidence
And in fact, I do have seasons in the United States.
flu season, for just Wisconsin the information for this year's
Wisconsin actually has one of the best influenza surveillance
systems in the entire country.
2007-2008 flu season, that And what we see for this year's
down off of peak flu season, we're just now starting to come
occurs right at the end which foof February, usually
into the beginning of March.
If we go back and look at the last three flu seasons, we
notice that of all the samples
the percent positive rate is between 25 and 30%
over the last three flu seasons.
the 2003-2004 influenza season, we see that the prevalence of
flu that year was much higher.
why that was? Does anNope?remember
Well, the reason is that
administered in the 2003-2004 the iseason was actuallyat was
not a perfect match to the circulating viruses
that were in humans that year.
we call a trivalent vaccine. So the influenza vaccine is what
whole influenza viruses contained in that vaccine
given to you to stimulate your immune response,
so that should you actually come face to face with the
real thing, you'll be prepared
Now, every year, well I should and you'll be protected.
depends on how well matched say the vaccine strains arecine
to the circulating strains. And every year,
the World Health Organization right around spring time,
has to make a guess,
prediction on what flu strains or an educated guess or
to protect from tthe upcoming flu season.
From the time that prediction is made by the World Health
Organization to the time that the flu season actually hits,
six months will have past.
is enough time for a new strain of influenza to emerge,
and to become dominate
and be different enough wifrom the vaccine strainon,
so that you won't be protected. Again, this is what happened
in the 2003-2004 season.
happened in this flu season. And this is actually what
of this year's flu vaccine, only one was well matched.
So this year we had a roughly 40% effectiveness to our vaccine
when normally we can benefit
rate in our vaccines. from However, like I said,eness
it's still a good idea
even if the match isn't perfect. to get your flu vaccine
for this. Number one, you're still going
to be protected against the strains that are well matched.
And number two, there's some
that can occur. So even if the viruses aren't
perfectly matched, if they're kind of close enough,
you still get some protection.
than no vaccine at all. But every once in a great,
great while, an influenza virus will emerge for which
the human population has never
previous immunity to, seand for which the vaccineny
doesn't protect against.
influenza viruses can cause what we call pandemics.
And a pandemic is a worldwide episode of disease that affects
a majority of the world's population.
And of course, the most notorious influenza pandemic
was that of the 1918
This virus that caused this disease was so deadly that it's
estimated that 40 to 100 million
in the roughly one year that people died worldwide
This disease affected almost this virus circled the planet.
for the people every aspect of everyday life
Schools and shops who had to be shut down.me.
University buildings were converted into large
mass clinics, like the one
the University of Iowa seen here taken from
for the mass number of people duriwho were coming downcare
with this illness.
been held, because not enough Nocaskets could be made foren
the number of people dying. And normal activities, like just
spitting on the ground
people were so scared of contracting and spreading
the disease.
was going on at the same time Acthat this pandemicI
was hitting the world.
more deaths were due in the war Andto the influenza virushat
than they were
In fact, this virus was so to actual casualties of war.
it actually dropped the average dealife expectancy for humans919
in the United States
And we see it as this big dip on this life expectancy chart
from 1900 to 2001.
that viruses like this However, I want to emphasize
We hardly ever see disease are extremely rare.
And in fact, a lot of the of tinfections and deathsead.
that occurred because of
were due to secondary bacterial infections, which
at that time there were no
Which now, of course, anwe have the antibiotics, andh.
we experience a much lower
The 20th century mortality rate from influenza.
Yes, question? saw four major flu pandemics.
I mean, how come it didn't >> What made it go away?
after the major pandemic? Why didn't it hang around?
We're not entirely sure.
are speculated why the 1918 flu Thejust kind of stopped.hat
Number one, the virus seemed to strangely target
very young people.
Well, I shouldn't say
viruses target the very old Normand the very young.sonal
But this virus targeted people
of their life, who had strong, who were in the prime
And it's suggested that perhaps so many of those people
ended up dying, the virus kind of ran out of targets
in the human population.
was actually an avian virus. Another idea is that this virus
virus. It wasn't a human specific
to the human system. So maybe it wasn't well matched
the humans weren't And so, again it just wasn't,
for this avian specific virus. the right target
not being enough humans, But I think the idea of there
dying from it, that the virus beran out of kind of substancep
to work with. So as I was saying, there were
four major flu pandemics
Of course, it started with in the 20th century.
In 1957, we saw the emergence tof the Asian flu, which wasc.
not nearly so deadly, but did end up affecting people
worldwide, as well. The 1968 Hong Kong flu
was the next one. And then in 1977, we had kind of
sort of a pseudo influenza
the Russian flu, because it was speculated that this virus
was leaked accidentally from a Russian laboratory
and introduced
And what we see here is that into the human population.
frequency, we had been with the roughly ten to 20 year
pretty regularly experiencing influenza pandemics
And after the '70s, these thpandemic strains of flury.
kind of went silent in the human population.
We're not entirely sure why,
of scientists to predict that we are currently overdue
for an influenza pandemic.
to the emergence of the H5N1 Avian influenza in 1997.
So far, this virus has killed only 236 individuals, which
doesn't seem like a whole lot,
is currently at roughly 60%. but its mortality rate
epidemiologists, researchers, as well as healthcare workers,
have predicted will be
of an influenza pandemic. So I kind of want to go now
into taking a closer look at these H5N1 viruses,
and looking at what makes them
potential to cause a pandemic. special and what gives them
about H5N1 viruses? One of the big things is
that these guys cause an increased severity of disease
in people they happen to infect.
symptoms that seasonal influenza We already talked about the
but when we look at patients causes in people,
with H5N1 avian influenza they experience something
far worse.
like acute respiratory These people get things
viral pneumonia, distress syndrome,
In rare cases, we see people multiple organ failure.
and encephalitis. What's really interesting
about H5N1 infection in humans
we see the virus has an increased ability to replicate
faster in human hosts,
outside the respiratory tract. and also to spread to areas
actually isolated H5N1 viruses So in animal models, we've
from the kidneys, as well as from the brains of mice,
That's not what we see normally with seasonal influenza.
Perhaps the most alarming thing again about these viruses
is that they're currently presenting a roughly 60%
mortality rate in people. This is in contrast to
the normal seasonal influenza mortality rate, which hovers
around .1%. So in addition to the worsened
clinical manifestations of H5N1 influenza, these viruses
are also exhibiting an expanding geographical range.
H5N1 arose in Hong Kong in 1997,
2002-2003 the virus stayed and then from '97 to about
of China. After 2003, it started movingn
largely throughout
But not until really 2005 or 2006, did we see the virus
start to disseminate
And so here in 2006, which greatly over the planet.
we see H5N1 geographical is what this maps represents,
and poultry, which is indicated by the light red countries.
The dark red countries indicate those countries that had
recorded cases of H5N1
and in humans. in wild birds, poultry
had moved largely throughout We see the virus in 2006
and into Europe, and had just Astarted to show up in Africa.t
If we move ahead now to the current situation in 2008,
we see that the geographical
even more. distribution has widened
dominated by this virus. Pretty much, Asia has been
everywhere there, but only Europe, it's pretty much
The Middle East, most countries have started to report H5N1
cases.
as well as avian cases And now Africa has human,
One thing I want to note showing up there, too.
this virus in the western hemisphere at all.
Although some scientists
a matter of time before birds that migrate between Asia
and North America may bring the virus over.
Is it seasonal, as it is
Yes, H5N1 has a seasonality, in the United States?
Okay, so one of the other concerns with H5N1 influenza
is that this was the first time we had ever really seen
a truly avian virus jump directly from an avian host
into a human host.
viruses is that they're Whavery species specific.nza
So for example, an avian specific virus
normally usually only infects bird species,
whereas human viruses normally
We do know however, that all only infect human species.
within the natural influenza subtypes can be found
aquatic birds. zoonotic reservoir, which are
actually distribute the virus to all different species
of animals. However, the transmission
of avian viruses to humans
Rather, for an avian specific virus to move into a human
it first usually has to go
And oftentimes, this is the pig. through an intermediate species.
a little bit more about pig infections after I'm done.
But the pig is able to adapt
to the human system, and allow the avian viruses
And so, in 1997, infection of the human host.
they completely bypassed when the H5N1 viruses emerged,
and moved directly into the human host causing disease.
We think that the avian viruses that did this were not
well adapted to the human host, and as a result,
this may be part of the reason
and cause such horrible disease. why they are so virulent
bird viruses get into people? Well, the biggest factor
is probably the very close
and people in Asia. Asia boasts probably the world's
highest density of humans,
densities of birds, too. as well as some of the highest
in their home, they sleep with And people live with their birds
to their live birds markets. them, they bring them everyday
images look almost ridiculous to us, but it's how they live.
Bird farming is very much a way of life for these people.
So not only is this virus devastating them in these parts
of world, because humans
it's also devastating them are getting sick from it there,
is being taken away when these because their way of life
and they have to be massively culled or killed
to try and contain the virus. So in addition to
an expanding geographical range to H5N1 influenza,
the virus is also presenting
We know that H5N1 can infect an expanded host range.
as well as humans, wild birds, domestic poultry
and surveillance efforts but more recent research
can also move into have found that H5N1 viruses
These include dogs and cats, other species as well.
leopards and tigers, as well as what we call palm civets,
which is a raccoon-type animal
So the increased host range also gives this virus
the increased possibility to become a pandemic virus.
So to kind of put into
that have occurred perspective the major events
I have a timeline here. Humans first came into contact
with H5N1 in 1996 when it was isolated
from a farmed goose in China. But it didn't show up in
the human population until 1997,
human cases in Hong Kong. w18 people got sick from it,d
six ended up dying. Yes?
How did they find it in '96,
looking for it? >> Right, no there are constant
influenza-- Because influenza is a disease
that's been affecting humans
we've been getting sick from it ffor a very long time.,
And so, there have been more severe and less severe
influenza cases throughout
with the virus. So, constantly within the last,
probably, since the virus was identified in the 1930s,
there have been surveillance
what kind of viruses circulate efforts going on to monitor
and then upon discovery that the virus was also harbored
within animal hosts as well,
and within humans to see what kinds of viruses
are continually circulated
I think it was probably just in these hosts.
that found this new subtype a comthat had emerged.effort
After 1997, H5N1 kind of
population for a while. Until February of 2003, when
two more humans came down from it in Hong Kong again.
They had traveled to China
And it was believed that they picked up the virus in China
and brought it back with them.
Later in 2003, the virus One ended up dying.
into other species of animals, demonstrated its ability to move
and two leopards infecting two tigers
And these animals were fed that actually died from it.
This also demonstrated infected chicken carcasses.
could be passed or transmitted and suggested that H5N1
In 2004, the virus spread widely through food products.
first account of human-to-human thrtransmission in Thailand.our
And this kind of started
now the virus had acquired to scare people, thinking that
throughout the human population, the ability to move easily
before we had a pandemic and it was just a matter of time
But it didn't happen. In 2005, the role of wild birds
was kind of confirmed in H5N1 transmission
at Quinghai Lake in China, where
in one big event. oveAnd prior to that, it wasely
uncertain whether wild birds
the virus to domestic poultry were able toor not.and transmit
From 2005 until the current day,
throughout Asia, H5N1 continues to spread
the Middle East, the Pacific Islands,
Currently, we have experienced Africa and Europe.
Those numbers 373 hare still tallying up.ths.
Where exactly this virus is going to lead us in the future,
we're very uncertain. But I kind of want to summarize
the current status of H5N1
Like I said, we have roughly influenza worldwide.
Most of these human cases a 60% are occurring stillumans.
in Southeast Asia,
African countries like Egypt, which has had 47 human cases
in the last year. We see an expanding
geographical range. However, I want to emphasize
again, we haven't yet detected
The virus has an expanding H5N1 in the western hemisphere.
very limited human-to-human transmission has been observed.
And this leads us to conclude that H5N1 was not yet fulfilled
the prerequisites to becoming a pandemic virus.
What do I mean by prerequisites?
to become pandemic, there are Wekind of three conditionss
that have to be met in order for that to happen.
Number one, a novel influenza virus must emerge into the human
population, for which we have little or no immunity against.
Second, the virus must be able
and cause serious illness. to replicate in humans
be able to establish efficient And three, the virus must
Now, H5N1 has fulfilled the humfirst two conditions.ion.
But, of course, we have not yet seen it
go easily from human-to-human.
in the influenza field And in fact, recent research
for H5N1 viruses to acquire haefficient human-to-humanr
transmission, they would be making a great trade-off
in virulence. So in other words if we were
able to start transmitting
the virus would probably not be tnearly as deadly as what
we're experiencing right now. The question, probably at the
forefront of most of your minds is should we be worrying
about H5N1 influenza? And my advice is I think
we should be vigilant of the worldwide situation,
but I don't think we should be
pandemic fever just yet. losing sleep or getting
carefully. Consider reported statistics
rate to this virus, which is We're reporting a 60% mortality
we've ever seen in the history higher than any flu virus
they're probably far more bird flu case cases out there
than what is actually getting reported
to medical institutions.
and morbidity rates may be So the actual mortality
than what we know of. Also, we haven't yet found it
in the western world, so we don't need to really
lose sleep on that
And this is in face of very vigorous surveillance efforts.
Currently, we have people all over North America who are
trapping and swabbing wild birds
actually come into our country. tAnd again, the virus cannotht
yet transmit person-to-person.
eradicated H5N1 on their soil. And also, some countries have
Well, for example, Japan had How have they done it?
And what they did was H5massive vaccination efforts..
They vaccinated not only
not H5N1, but they got their people against obviously,
normal seasonal flu vaccines. crAnd also, they ended uper
doing vaccination efforts of their poultry as well.
On top of it, once H5N1 was detected in their poultry flocks
they ended up killing those flocks off very quickly
to try and contain the virus. So, if H5N1 were to occur and
show up here in North America,
we would have a doomsday. We would be able to potentially
contain the virus.
I mean, you talked about >> How is it transmitted?
from being fed. the two l>> Right.nd tigers
So was the transmission-- It must be raw?
Yep, they were raw
It wasn't cooked, they were raw. chicken carcasses.
cooked. If you actually cook or heat it,
the virus it dies, it's done. So if you eat raw poultry meat,
you're at risk
So it isn't transmitted for respiratorily?nza.
Not necessarily.
be. It doesIt's respiratoryhave to
most of the time, but remember
influenza as a gastrointestinal that birdsdisease.y present
And so they can actually
in the fecal oral route. shed it through their feces
through their feces, actually, And we can pick it up
Also, the FDA last year, in this case.
approved an H5N1 vaccine. This is not commercially
available.
but it's currently You can't go out and buy it,
in the event that ban H5N1 outbreak would occur.y
So we have made strides on this.
until very recently. This was not available
is what is being done So about H5N1 worldwide.ion
And I really kind of
about what's being done right here in Wisconsin, because
of think a lot of the efforts that are going on here
in Wisconsin kind of reflect
The biggest thing that's going the global efforts.
thing that's stressed is on right now, and the biggest
surveillance of birds, very, very strict and rigorous
and even human influenza cases, so that we can be aware
of an H5N1 case the minute that it would
come into North America.
right here in Madison, So here in Wisconsin, actually
of Hygiene. wAnd this institution conductsb
statewide influenza surveillance
So all the samples, all the aspecimens of influenza illness
are sent to the State Lab of Hygiene.
They test these samples,
people are having this year. find out what kinds of viruses
ultimately, to the World Health That iOrganization. sent,
It helps to decide what the vaccine selections will be
for a particular year.
Diagnostic Laboratory does very much the samey
what the Wisconsin State Lab
except in animals. of Hygiene does,
a backyard flock of birds, So for example, if you have
are kind of dying off, and you find that some of them
They come pick up your bird, you could call these guys.
and let you know whether test it for you
In addition to doing you have bird flu in it or not.
in animals, the Wisconsin Veterinary Diagnostic Laboratory
also does training programs abroad in countries that are
most hard hit by H5N1 influenza.
out to Thailand and Indonesia and train the people, the
medical personnel over there, how to use the most up-to-date
and cutting-edge
better the surveillance efforts diin those countries.elp
And again this is right here
The U.S. geological survey on the UW campus.
Department of the Interior. And we have a branch here in
Madison, who has people,
taking samples from wild birds always up in Alaska again,
that have migrated into Asia to see if any of those birds
into North America. will bAnd we haven't seenluenza
anything yet. Then finally, I don't believe
that good counter measures
H5N1 influenza, can be developed to seasonal influenza, or even
that looks at how the virus replicates, how the virus
interacts with its host,
and so on and so forth. theHere at the University ofirus
Wisconsin, we have at least three major influenza labs
that do basic and applied influenza research.
And our lab is actually one of those.
I work on campus here in the laboratory
of Dr. Stacey Schultz-Cherry. We are a World Health
Organization collaborating lab. And our research focus is on
influenza pathogenesis. What that means is how the
virus actually makes you sick.
here on campus. AThis is actually a pictureu
of my lab-mate Jeremy Jones in
where we do all of our work our with bird flu viruses.ity,
So we are particularly
and viral factors involved interested in the cellular
My personal thesis project is focused on one particular aspect
of the immune response
and H5N1 infection. We've been successfuln
in developing at least one
effectively prevented H5N1 flu anti-viral peptide that has
Then finally, we collaborate from infecting mammalian cells.
companies to develop better withdiagnostic testsogy
for seasonal flu
And so with that, I would like to thank all the people
who let me come and speak today.
Stacey Schultz-Cherry. My lab and especially my PI,
for asking me to come do this with him again.
It's always a lot of fun. The University of Wisconsin
Biology Outreach Program. And, of course,
the Plato Frontiers in
And to all of you for coming Life Sciences Seminar Series.
for the last half hour. So without any further adieu,
I'll take any questions that you guys may have.
Thank you.
that you had on >> Tabout the immune...?lide
Yeah. >> Could you elaborate a little
bit about your own particular thesis on immune response?
Yeah, I work with a protein in the body that's called
transforming growth factor beta,
And what we know about TGF beta is it's a very important
regulatory molecule in the human immune response.
We found that influenza viruses are able to differentially
modulate TGF beta.
we found all influenza viruses What's interesting is that
TGF beta, which serves are actually able to activate
to the host to say, ahey, you're infected, starte
implementing immune responses to get rid of this.
So all flu viruses activate it
H5N1 viruses. They don't trigger the sensor.
And we're trying to figure out
What's different about why exactly that is.
don't alert the host as well the bird flu viruses that they
And how can that play out asin the outcome of infection?.
And so, we've found that animals
Actually, if we deplete TGF beta who--
a non-lethal influenza virus, that infection becomes lethal,
much like the H5N1 viruses. And additionally, if we infect
animals with lethal influenza viruses, and we add back
TGF beta, we find that now
So it seems that TGF beta is playing a very critical role
in modulating the host immune response, and actually playing
a role in influencing the outcome of influenza infection.
So that's kind of my personal project and what I'm working on.
Yep?
The flu shot >> A couple questions.
Yep. has three different viruses.
how many different strains >> When flu hits the country,
Is the three an arbitrary number really are going on?
of some sort in the choice. >> Yeah, I actually don't know
how many are circulating
at any one given time. in the human population
reason that three is chosen is What we do know is that the
of the three major subtypes. they're kind of a representative
specific subtype of influenza. So when I say H5N1, that's a
known subtypes. The H actually stands for
one of the proteins on the surface of the virus.
The N stands for
There are 16 known H's, nine known N's..
And you can have any combination
So that gives you an idea of of those.
Not all those infect people, how many subtypes are out there.
vaccine because they represent but we choose three for the
that are known to infect humans, the three major subtypes
and a B type influenza virus. And so, those are the common
circulating human strains,
Not to say that other strains ancan't move into the humanme.
population, but that's what the vaccine's based on.
A second question, is SARS
Yeah, SARS actually presents related to this in any way?
manifestations as influenza. with very similar clinical
are similar in a lot of ways, but they're primarily
very different. Influenza is what we call
a negative stranded RNA virus.
that's inside that virus. That's bSARS is actuallyeic acid
a positive stranded RNA virus.
very different. They're transmitted very much
the same through the respiratory
a human pathogen. rouAlthough, I think it canlly
be found in civets, as well.
they are very different viruses. But, no, at the very basic level
to be protected from SARS And if, for example,pect
you got the flu vaccine.
cross protection there. There wYep? be no
What factors, or how did they determine the forecast of which
viruses they're going to choose for the vaccines in advance?
Right, so what happens is I think there are,
I forget the number,
major surveillance institutions throughout the world.a
There's one in Australia. There's a couple of them
in Asia.
which is related to the CDC Onor the Centers for Diseases,
Control and prevention. Throughout the year and
throughout the influenza season,
surveillance. And this is collecting samples
on a massive basis, analyzing those samples and finding,
really trends and what
in the human population are. the dominate influenza viruses
surveillance efforts tell us, that's how the World Health
Organization collects all that data in one centralized
location, reviews it and
this A Wisconsin type H3N2 virus says, okay, it looks like
strain this year for the looks like it's the dominate
going to put in our vaccine. flu season, that's what we're
is the dominate type. It's the result of the whole
last flu season year's worth
and seeing what the trends are of collecting data, analyzing it
in humans. in influenza circulation
in the way flu >> So are there patterns
Yeah, and it seems that, travels around the world?
why influenza is seasonal, you know, people always ask
to show up in December? Some groups have suggested
that there is a relation
and when it moves over. to I think it's more ofia,
the dry and cold weather
and that's why it tends to be keepsa seasonal virus.ether,
One thing to add
vaccine types. about the choosing the different
there's a little blip Oftwhere the viruses actuallyn,
infect more people
before it disappears. And that little blip, often the
virus has changed a little bit. And that's pretty similar to
what the virus will be like the next year when it comes around.
So that's also pretty helpful,
Yep? sometimes.
population we have, and the gastrointestinal possibilities,
is anyone monitoring them in particular?
Yeah, and actually again
Department of the Interior's this goes back to the U.S.
in Alaska, because those sites efforts up in Canada, as well as
sites of where H5N1 would woulenter North Americaicted
or our country. What they do, is they have
people who go out in the field
They trap these birds and take every day.
it's a gastrointestinal disease whafor the birds, and thenause
they culture that swab and
to determine end up sequencing the viruses
So yes, there's a very vigorous surveillance effort going on
in the northern part
Okay, well if there's no more questions,
I'll let Al take it over. Thank you very much.
( applause )
Can you hear me all right? >> All right, thanks Christina.
My name is Al Bateman. Okay.
laboratory also here at UW. I'mI'm also part of the CMB,on's
Cellular and Molecular Biology
And, oh, yeah, and little bit about me, sorry my background.
I'm also from Wisconsin.
It's near La Crosse, I grew up near West Salem.
I went to undergrad at near the Mississippi.
I majored in chemistry St. Olaf College in Minnesota.
So, I put those two together. an( laughter ) actually.
A little random, but it was a good combination though.
I actually put those two
I studied in Norway for a year. I worked in a laboratory there.
After that, I've come back, and for the last two and a half
years now I've been at the UW studying swine influenza.
So I'll tell you a little bit background about what exactly
it is, and then I'll actually go into a little bit of the
research that I do, and some
So with that, first of all, offor my talk I'll start out.
like I said, with the basic about what swine influenza is.
Basic information about viruses,
the different species that influenza viruses infect.
This might be a little bit
it's a little different angle, of a repeat from Christina, but
I'll specifically talk about I think.
and then I'll go on to why swine influenza for a while,
It's a pig pathogen. swine influenza is important.
so there's a possibility for There is a zoonotic potential,
And also I'll talk about pig viruses to infect humans.
in possibly generating the role that pigs can play
Oh, yeah, I don't know if this pandemic influenza viruses.
I just included this picture comes up very well, but
It's one of the viruses that because I'm kind of proud of it.
And we just got that picture I work on in the lab.
I'd include it. So viruses are defined
as obligate intracellular parasites, which means they
cannot replicate by themselves. But when they're inside
of a cell, as Christina said, they take over the cell
and use it to make more copies
Viruses infect all different of themselves.
and other mammalian species to insects and even bacteria.
Basically, if there's a type
one type of virus of cellthat infects it.t least
Viruses are also very heterogeneous.
They vary in their size,
It's either the DNA or the RNA shape, and their nucleic acid.
Shown here is just a depiction that they have inside them.
Right here, of is a tobacco mosaic virus.es.
It infects plants.
and right here's an influenza. This one infects bacteria,
In terms of their size, Sthey're very small, but just.
for a little comparison here, here's an influenza virus.
When influenza infects humans we obviously get very sick.
So consider, if you as a person if you were the pathogen,
if you were the virus,
your host would be how big do you think
Do you have any idea? >> As big as the earth?
He's on top of it, wow. That's roughly how big
the pathogen that you would have to infect would be.
So, to me it's just amazes me how small viruses actually are,
and how they can still cause
It's quite impressive and a little scary, too.
Do all viruses
Not all of them do. Like here are some of what
the other viruses look like.
They're all fuzzy. But influenza is--
Some of them are fuzzy, yes. ( laughter )
viruses are about roughly a thousand times smaller
than even one single cell.
a little bit, but the virus, And Christina went over this
it binds to a cellular receptor on the surface of the cell.
It then gets endocytosed, it's called,
when it enters into the cell. This is really complicated,
but basically this is all the replication steps influenza
has to undergo. This is maybe not even
all of them, but some of them.
progeny virus, it then exits To produce more infectious
So influenza viruses, tthere are three types.
A, B and C. Type A is the most
serious burden, both
I'll just be talking about economically and health wise.
But Christina briefly mentioned ithat B also does infect humans.
on a yearly basis.
This means that they contain Influenza viruses are segmented.
segments of RNA. their genes on eight separate
to reassort. And this allows for the virus
different viruses infect And this means that if two
segments can kind of just play the same cell, these different
reassort to produce a new virus with a different combination
of the segments.
that more in a little bit. And I'll talk a little bit about
on the outside of the virus are the hemagglutinin or the HA,
and the neuraminidase or the NA.
And as Christina had alluded to,
of the both the HA and the NA. there are many different types
are present in the wild water foul population.
And the subtypes are based on these two, so humans
are commonly infected by H1N1 and H3N2 viruses.
Whereas the possible
was talking about is H5N1. avian influenza that Christina
have been seen. I think there are a possibility
of 256 combinations of different
of them have been seen. Again, this is the same sort
of wheel of misfortune
influenza viruses can infect. oWe have all of them presentt
in the wild bird populations
interested in the Olson Lab, and the ones that we are most
so the interspecies transmission is the swine influenza, and
wild birds and humans. between pigs and poultry,
is constituted of many different So swine influenza actually
I'll just talk about the subtypes of influenza.
North America, because they're different subtypes in
of the world. For most of the 20th century,
swine influenza is mainly just caused by the H1N1 virus.
But then in the late 1990s, a new type of virus
called H3N2 virus emerged.
by the reassortment AnI just talked about.n
Some of the H1N1 segments,
and some segments and from human viruses.avian
Because it was from three different species, we call these
triple reassortment viruses.
spread throughout the swine population in North America.
But as you can probably tell
there, the story continues. There's been more reassortment
from in between the H5N1
We call these second generation and reassortment viruses.nts.
Basically, most of the genes
the H1 the N1, or both of them, from these will be called
classical swine viruses.
these R for reassortment, rH1N1. So now we have H1N2, H3N1 and
of viruses have been isolated from pigs in the past few years
in North America. Most recently, there's even
another one that's been isolated.
This is an H2N3, which is a reassortment of one of these
viruses with the hemagglutinin
from the avian virus. So basically the take-home
message is swine influenza
there are many different is not one particular virus,
But yet they only constitute subtypes.
and also the N1 and the N2. That's mainly what circulates
in the swine population.
different subtype of influenza However, regardless of the
influenza virus infects pigs, the are pretty similar.e the
There's a sudden onset of disease and the pigs are quite
inactive, they huddle together. They often sneeze and cough.
They have a pretty high body temperature.
They have rhinitis, and they lose weight.
But then about a week after the onset of the disease,
they just suddenly recover. So it's a sudden onset
and sudden recovery.
high morbidity, meaning that And influenza in pigs has a
almost 100% of the pigs won that farm become infected,
and become sick.
low mortality, meaning that of all the pigs that actually
get sick, less than 1% actually die from the virus.
So these clinical signs might seem pretty similar,
might sound quite familiar, because they are actually
pretty similar to the symptoms
typical seasonal influenza. that hThere are actuallyy have
many other similarities between swine and human influenza.
In addition to the clinical signs and symptoms,
they are the same main subtypes.
swine influenza is mainly H1 and H3, and N1 and N2, and
different combinations of that. And the two main subtypes
that circulate in humans
The virus replicates in the respiratory tract of both humans
and swine, whereas it replicates
of most bird species. iAnd while influenza virusest
are mainly species specific,
or relative to all the different relatively, to other species,
can cross species, directions that influenza
from pigs to humans and from humans to pigs
is relatively common. And in our lab, we've shown
that some viruses have
in both human and swine cells. pretty similar infectivity
again in a little bit. I'll get back to that
Is the transmission, again, respiratory, or like if you have
a sick pig and you ate the meat,
That's never been documented. It's strictly respiratory.
Yep.
to cook your meat. But it's still a good idea
of swine influenza. First, it is a pig pathogen
so it is a pretty serious pathogen.
It causes them to lose weight and get pretty sick.
It's a pretty big economic
because it takes more time burden on the swine farmers,
up to market weight, and it's a pretty big economic burden.
The other two I will talk about now.
Zoonosis comes from the Greek words of zoon and nosos.
It's defined as an infectious disease that's able to be
transmitted from animals, this is either wild
or domestic animals,
And just for a couple recent into humans.
the Ebola virus, or HIV. examples are SARS,
actually viruses too. ASwine influenzal
also has zoonotic potential when it infects humans.
There are quite a few isolated
They're mainly when a swine inciinfluenza virus infectsars.
one person. And this is usually an animal
caretaker like a swine farmer.
to transmit from human to human They hvery often. shown
But there was one incidence in 1976 in New Jersey, where
an H1N1 swine virus spread
of the soldiers there. and infected quite a few
potential of swine influenza. As for the ways that pigs could
be involved in the generation of pandemic viruses, shown here
are three possibilities.
subtypes of influenza are found in the wild bird population.
And right now it's only the H1 and the H3
that are circulating in humans. So if any of these other 14
are able to infect humans and transmit among humans,
that could be the next pandemic.
about the direct transmission from a bird into humans,
but also there's this adaptation
where an avian influenza virus hypothesis,
And upon replication in pigs could infect pigs.
more infectious for humans. And the third possibility
is reassortment, where an avian virus and a human virus
could co-infect a pig,
to both types of viruses. And if they infect the same cell
of that pig, this is
the viruses could undergo and produce a new reassortment virus
that could then infect humans.
about the adaptation hypothesis, I'm going to talk a little bit
that we've done in our lab. And this is specifically
talking about H4N6 viruses. It's just another type of virus.
H4N6 have mainly been found in the bird population.
Actually, have always been found
species until a couple years ago just in birds, not in any other
and another collaborating lab isolated them from pigs.
So normally they're just
But the interesting thing about the one isolated from pigs
is that it had two mutations. And these mutations were in the
HA protein, the hemagglutinin.
positions 226 and 228. And they were at
amino acids 226 and 228. They were actually at
blocks of proteins. AmSo just different partsing
of the proteins.
had these two mutations, we wondered if maybe it was already
undergoing this mutation, to possibly become
more infectious for pigs, and more infectious for humans.
So like I said, this is what
And so, to try to mimic this we isolated from pigs.
any sort of selection pressure in the lab to see if there was
we took an avian virus for this mutation,
We have a system to grow and we infected swine cells.
infect pigs all the time. swiIt's a nice model system.e to
We put it on swine cells. We then took it back off,
took the progeny virus, the virus that's produced
from the pig cells
of pig cells. And we did this ten times
to see if we would get these
So, to do the comparison here, same mutations that we saw.
has positions 226 and 228, the avian, again,
whereas the mutant has a Q and a G,
had an L and an S. that we found out of pigs
from P0 down to P10. And so there's a passage
did not change at all after the ten passages.
But the 226 at P3 started to change from Q to L,
and by P4 it was
And then it stayed L completely changed to L.
So we think this is the same the whole way until the P10.
that we had isolated. So we thought that this 226
might be pretty important.
the cells, these pig cells, with either the virus that we
started with or the mutant
Red is infected cells here. This is just the amino acid
at position 226,
So we had the avian and then we had the double one.
But we also had a single one
and we had a single one that just changed the 228.
And basically, you can see
the amino acid at position 226 this correlation between
Whereas, if it's Q, the viruses have quite low infectivity.
And if it's an L, the viruses have a much higher infectivity
in these cells. So yes, this amino acid at 226
does definitely have--
for infectivity. This mutation does have effects
to be able to infect humans? What about this last part here,
in vitro system with human Well, recently we also have an
infect humans, obviously. So we did the same thing.o
Here are the swine cell infections again, and
here are the human infections.
where you have the same high-low, high-low infectivity.
The infectivity in human cells
the amino acid at position 226. So it does lend credence
to the possibility of this
of a new pandemic virus. adaptation hypothesis
to completely scare you guys. You don't have to worry
too much. These H4N6 viruses
are not highly pathogenic,
infected humans. unlike the H5N1 that have
There are possibilities that the pigs that these viruses
were isolated from
with other viruses or bacteria were also infected
together made the pigs sick, that could have possibly
we noticed this outbreak. None of the pigs
on the infected farm died.
beyond the initially infected And the virufarm.id not spread
So there's not a huge risk here.
One last thing. BuThe H3N2 viruses commonlyty.
circulate in humans.
by becoming infected, or from Anbeing vaccinated, we haveher
antibodies against the H3 virus.
to H3 is actually H4. ASo there's actually been
some cross reactivity with the antibodies
that our immune system makes, that they could cross react
with the H4 viruses also. So even if these H4N6 viruses
could infect humans, and even spread it among humans,
it likely wouldn't be nearly as devastating.
It would likely be similar
that we see on a yearly basis. to the seasonal influenza
might not be the best idea. Bu( laughter )his still
As much as you like pigs. ( laughter )
So with that, a quick summary to say that swine influenza
does definitely infect pigs.
pathogen in pigs, and that also does infect people both in terms
of the zoonotic potential and the potential for the generation
of a pandemic virus.
subtypes. So, as Christina had talked
about, the surveillance of swine influenza viruses
is also very important
in the pig population and also for possibilities
that those viruses
And yep, as far as the could then transmit into humans.
it could be by reassortment, generating pandemic viruses,
a combination of the two. I thought I'd throw this out.
This is the type of jargon
just to be very specific. So amino acid 226 in the HA
of H4N6 influenza viruses determines infectivity
in swine and human cells. And hopefully now you have some
sort of idea of what that means.
members of the Olson Lab, So my mentor Chris,her
Jordy, Mark and Sasha.
Series, to the Biology Outreach Also toClub at UW, Seminar
and to Christina Carlson
So with that I'm going to put this up because it's priceless.
And I'll take any questions.
In addition to swine Yes?
this kind of study going on with rabbits, and squirrels,
and horses, and dogs? >> That's a very good question.
Horses, yes.
and has been known for decades. EquinAnd there are a coupleommon
different subtypes there. There are some people starting
to look at other wildlife species like raccoons,
to see if they get... Yep, exactly.
I'd say definitely the main ones
And the other thing with are avian influenza.
to lump it all together, avian influenza is we tend
species of birds, obviously. but there are many different
the ducks versus the geese, versus the swans, and what
the differences are between the different bird species
is also very important. I'd say one other thing about
swine, the reason why there's been quite a bit of interest
is because they are susceptible to both human and avian
influenza viruses.
of possibilities for this cross species transmission
to happen.
Where are your labs located? Any other questions?
They're both on campus. I'm in the Veterinary School.
Down beyond the Ag barn?
( inaudible ) >> That lab, is that in the new.
building? >> We will be moving there
shortly.
Medical Sciences Center. Currently, we are in the
hopefully we'll be in our new By the ebuilding. semester
Okay, thanks a lot. >> Thank you.
( applause
)