Bluetongue virus of ruminants

Bluetongue virus of ruminants

November 8, 2019 3 By William Morgan


Bluetongue virus is transmitted to its ruminant
host almost entirely by biting midges which
we call Culicoides. So this means it’s a
non-contagious disease so if you have an infected
sheep which shows clinical signs of Bluetongue
the sheep next to it will not be infected
by the virus, directly by passing on from
one sheep to the other. The virus can only
transmit if the biological vector Culicoides
biting midges are around.
The virus replicates in the insect and eventually
after a certain time period it will reach
the salivary gland. Once it has reached the
salivary gland the next time this now infected
midge feeds on a non-infected suitable mammalian
host or in the case of Bluetongue again ruminants,
sheep, cattle, it can then transmit the virus
during that blood meal back into the mammalian
host and then the virus starts its replication
cycle in this host again.
This is a really intriguing relationship because
it doesn’t function as a mere needle transmission
at all. There is more and more research for
example, that the saliva has a very active
role potentially in pathogen transmission
because these insects have to salivate to
stop blood coagulation and immune responses.
So their saliva is pharmaceutical active,
it contains anticoagulants because if they
otherwise would try to feed the blood would
immediately clot and then you can’t take
it up but by having these bio-active molecules
in their saliva they can prevent this blood
clotting and they are able to take up a blood
meal.
Because there it is a non-contagious transmission,
classical methods we use like preventing contact,
restricting animal movement, although they
are still necessary they have a far less impact
on a vector-borne disease. Animal movements
are important to not dislocate the virus throughout
an entire country, so of course if you moved
an animal from southern England to northern
England, you could almost create a second
outbreak.
However on a local scale, once the local insect
population is infected they will fly, they
will not stop, you can’t restrict it, you
can’t say excuse me you are now on movement
restriction. So even if you do have animal
movement controls, the moment that virus is
in the local insect population you have lost
it because it will still be able to be transmitted,
those insects will still fly and infect neighbouring
farms.
So this is one of the challenges of dealing
with a vector-borne transmitted pathogen and
this is why if you are a free country and
you are fearing the incursion of a vector-borne
disease it is so important to catch it early
because what you are trying to do is find
it and remove those animals or at least get
them out of being exposed to so many biting
insects before the local insect population
is completely infected.
The Pirbright institute has an insectary where
we breed several insect species, mosquitoes
and some biting flies’ ___ and also Culicoides
biting midges. In our Bluetongue research
which is mainly Bluetongue pathogenesis research
or transmission research or immune response
and vaccine research, we do the vast majority
of our work with those mammalian hosts which
are in nature infected and affected by this
virus, so we use sheep, goat and cattle – Because
if you carry out research in something as
complex as pathogenesis – so where is this
virus going and how is it causing disease.
Something like the immune response which is
very species specific we feel that it is an
incredible advantage to actually be able to
use the host which is affected by this disease.
We would obtain our study animals like sheep
or goats or cattle from a commercial farm.
These are normal farm animals and that the
moment they come into our isolation units
they are incredibly monitored. So depending
on which type of study we do we would treat
them, we would give pain killers.
One question which is often raised when we
talk about of work and describe our work is
could we do our research without using animals.
So we do a lot of work with primary cell cultures
where we just get blood or samples from animals
which are put down anyway, to establish primary
cells, to establish organ cultures and we
carry out infection studies of these cells.
Even we have a project where we also assess
the response of these cells to insect saliva
to already get an idea what is going on, what
kind of cytokines are being made, how do they
respond, is there a difference when the virus
is on these cells, with and without midge
saliva so we have developed a method to collect
midge saliva by making them spit into a filter
and we can wash off the saliva. We have a
really active project to get our research
to a level as far we can by not using animals
but there is only so far as we can go.
When it comes to big questions like transmission,
when it comes to big questions like; is this
vaccine safe? Is this vaccine efficient? how
does the animals respond upon challenge? We
cannot carry out this work without the use
of live animals. The vertebrate immune system
is way too complex that we could ever hope
to replicate that fully in a model system.
There is always going to be a step where we
need the animal research because if you just
think of how for example an insect-borne virus
is transmitted with insects’ blood feeding
in the skin. The skin is the biggest organ
we have and is one of the most complicated
organ we have and then you have blood vessels
bringing all the cells and responding and
then it gets distributed to the entire body.
This level of complexity would almost be impossible
to create in an artificial situation and although
you can take it so far and reduce the numbers
which is the ultimate goal. There will always
be questions where we need the whole organism.
Currently the work we do on bluetongue virus
we use about 20 – 30 animals a year. Occasionally
when there is an outbreak of bluetongue virus
for example, in a country where this has never
been or there is a strain which is emerging
which we don’t know, then there is the potential
to do like an emergency study to be able to
characterise the pathogeneses of this virus
and to foster vaccine development for this
particular strain.
There are several vaccines against bluetongue
virus and to understand why we are still concerned
about developing other vaccines for bluetongue
virus we need to look a bit at this virus.
The virus has 27 serotypes, so far we have
discovered at the moment but they keep finding
more and the problem we have is that the protection
or the immune response up on either infection
or vaccination is serotype specific so what
that means if you vaccinate against BTV8 your
sheep or your cow is only protected against
BTV8. It is still susceptible to 26 other
bluetongue strains.
The vaccines which are available, are in northern
Europe inactivated vaccines, that is they
are safe, they are efficient and they have
been used successfully for example to eradicate
bluetongue virus 8 from the UK a few years
ago. They are monotypic, so they will only
protect against this strain, hence they are
fine in a situation where you combat a single
strain incursion. It gets more problematic
when you are in a country which has several
strains of bluetongue virus circling.
One big area of the research is to try to
find out how can we get a cross-serotype protective
vaccine because in countries like India where
bluetongue virus still have a big impact on
subsistence farmers especially in the south,
they have 10, 15, 20 strains of bluetongue
virus circling. So a lot of endemic countries
use a modified live attenuated vaccines. They
have several strains of live virus however,
it has been shown that they can reach levels
which makes them transmissible. So midges
can actually pick up the vaccine strain and
then testing some of them in British breeds
they also induce clinical signs. So whilst
some indigenous breeds have clearly evolved
with the disease and do not get sick to these
vaccines any more, we did not use them in
northern Europe because we could show that
to certain preparations they would till induce
clinical disease in the country.
So then when we test for antibodies we don’t
know does this animal have antibodies because
it go vaccinated or does this animal have
antibodies because it was infected at one
point during their life.
That makes control very difficult and then
another area with inactivated vaccines is
although if they are applied well in time
they are protected against the challenge of
the virus. The immune response is relatively
slow. An animal is protected sheep probably
after 3/4 weeks, cattle at the moment need
2 dosages so that would mean probably 6 weeks
until they are protected. So if you think
of an emergency vaccination where the virus
is already active, you could find yourself
in a situation that induction of immune response
isn’t quick enough.
So developing better vaccines which might
be quicker might again shorten that risk if
you need to use a vaccine preparation as an
emergency response. So these are all drivers
for improving the vaccine although in a one
strain outbreak situation and applied well
before the virus really gets going the current
inactivated vaccine available for bluetongue
will protect your animals and is a good way
of protecting your animals.
Another very important component of this virus
which is crucial to understand is that it’s
segmented. So its genome is arranged in segments
and what that means is if 2 strains of bluetongue
infect one cell they can swap segments, a
bit like influenza can. So we create this
virus not only creates variation by mutation
it creates variation by changing genome segments
which we call re-assortment.
The immune response to this virus is monotypic
so it is specifically to the serotype. Other
characteristics however are strain-specific,
so we can have a mild or moderate or virulent
strain of for example BTV1. When we have a
new outbreak, we by serotype have no clue
what this strain is going to do. Just because
it is a BTV8 strain does not mean that it
will be a virulent strain, we have to monitor
we have to see and sometimes we even have
to do an animal experiment to understand what
kind of strain are we dealing with.
Is this a virulent strain, is this a mild
strain, how quickly do we need to get a vaccine
out or if this is a mild strain, can we let
this go? This can obviously change very, very
quickly with re-assortment. You could have
a mild BTV1 strain encircling and a virulent
BTV8 strain encircling and then they infect
the same animal and suddenly they swap the
genome segment which is responsible for the
serotype that say BTV1 but then virulence
is on other segments and suddenly you have
a new BTV1 because your BTV8 strain has now
got that segment from BTV1 but it has remained
all the virulence of the other segments which
inside really make it BTV8 but on the outside
it has now become BTV1.
However it still does mutate and it does mutate
in this segment – this segment too which
encodes for the outer code protein which defines
the serotype and this is why we have 27 serotypes
but the strain landscape is far more complex
because it can chop and change all the other
segments and therefore render a vaccination
campaign useless within the exchange of one
genome segment.