Cases of Whooping Cough are on the Rise: Is There Anything we can do About it?

The Director of the Milner Centre for Evolution, Professor Turi King, talks to Professor Andrew Preston about his research into the group of organisms called Bordetella. The most prominent member of the Bordetella group is Pertussis which causes Whooping cough, a disease that is on the rise again.

Episode Transcript

(00:02):
Hello and welcome, you are listening to a podcast by the Milner Centre for Evolution,
at the University of Bath. I'm Professor Turi King, your host, and today I'm talking to Andrew
Preston, professor of microbial pathogenicity, about his research understanding how bacteria
cause disease in humans and animals.So, Andy, I'm always really interested in

(00:23):
knowing how people came to do the research that they do. So, was there something that triggered
it for you, to get into this area of research?I mean, I wish it was a more conscious decision,
but no, I was an undergraduate studying biochemistry. Part of the course was a
final year project, so I talked to cancer biologists, cell biologists… all sorts, but
ended up in a microbiology lab and that was that.And I think if you are a researcher, and I say

(00:46):
this to some of my tutees and they think I'm mad, I'm not convinced it really matters what it is,
it's the process. So, if you really are a researcher, you could be a researcher
in anything. But in many cases, you don't know anything other than what you've been exposed to,
in my case, it was microbiology, and that's what I've stayed in because it rings all the
bells for me, in terms of what I want to do.So, what is it that you're researching now?

(01:08):
So, at the moment we're primarily looking at a group of organisms called the Bordetella.
And the most prominent member of that group is Pertussis, and it causes Whooping cough,
which is resurgent in many countries worldwide. So, we're asking questions about what is
happening? What's the likely trajectory? And of course, can we do anything about reducing
the numbers of cases that we're seeing?So, what are you looking at with it?

(01:32):
In terms of broad questions, it's, how does Bordetella do what it does? So,
what's the interaction with the respiratory tract? How is it bind? How does it grow?
How does it overcome host defences? How does the host respond? And I think one of the interesting
things which maybe ties in with the Milner, is that Pertussis is really a very new disease,

(01:52):
probably only being around in its current form since the Middle Ages, and even within the last
100 years, we know it's still on an evolutionary trajectory, it's still adapting to the human host.
And we've done rather consequential interventions such as vaccination, which, again, even in the
last 20 years has left a strong imprint on this organism. And even since Christmas of this year,

(02:15):
we're seeing another change in the way that this bacteria has come back after COVID. And it's
doing new things, leading to some pretty large outbreaks and infant deaths in the UK this year.
So how is it coming back after COVID? What's causing that?
Pretty much all respiratory diseases, they depend on people doing what we do now, being close to
each other and breathing to transmit. Obviously, that was interrupted significantly during Covid.

(02:40):
The actual cases of Whooping cough largely disappeared from most countries where you've
got good reporting. So, we're interested in what happened during that time. You know, we think the
world shut down, the world didn't. Rich countries shut down; the rest of the world carried on.
And so, I think what we're seeing is a receding in developed countries of disease from elsewhere.

(03:02):
But those bacteria are slightly different from the ones we had pre-COVID. And so we're really
interested in trying to track what has happened, to see how if you sort of reintroduce these
bacteria into what is largely a naive population, because we haven't had any exposure for a while,
being able to sort of compare before and after, because I think we're going to see a different
pattern of disease going forward, with Pertussis, there were signs of it changing prior to COVID. I

(03:28):
think this is just really, reimprinted a, sort of, new host immunity pattern on it, and we're
waiting to see how it plays out in the long run.So how do you do that? How do you study that?
These are population effects, so we can do all sorts of fun and games in the lab
looking at the interaction between individual cells, individual bacteria. That's not really
the forces that play at the population level. We need these broad pictures of host immunity.

(03:53):
So, we're trying to work out how to follow these bacteria in people more closely,
because at the moment we're utterly limited to somebody reporting to a GP or a hospital,
with a severe case of Whooping cough. That's the notifications we get, and most of our
understanding about the way this bug is moving through human populations is by, perhaps, just

(04:16):
relying on those tip of the iceberg notifications.So, where's this bug in the human population when
it's not causing disease, which we think is probably a relatively small proportion
of cases. So, who's it in? Is it just within kids? Is it within teenagers? What's happening
in the older population? What portion of the human population might be carrying the

(04:36):
bacterium? And that's where probably most of the selection pressure is happening. How long do they
carry it? And who's transmitting to whom?So, we're trying to develop new studies and
new tools, so that we're no longer reliant on what is probably a tiny
percentage of the cases, which is classic cough.So, this is a thing, so there's vaccines for this.

(04:58):
So presumably people will not necessarily go on to develop disease in a big way, but they
can still be transmitting it, I'm guessing.So, this is one of the impacts that the human
intervention has had over the last 50 years. So, the first set of vaccines were wholesale
vaccines. You literally grow a massive vat of bacteria; you kill it and inject it.

(05:20):
And the advantage for that is it displays a whole range of targets for your immune systems,
thousands of targets, because that's the nature of a whole bacterium.
During the late 1990s, we switched to a subunit vaccine. So, five highly pure proteins
from the bacterium, for reasons of safety and reactogenicity of the vaccine, that's created an

(05:41):
entirely different focus for the immune system.So, whilst those vaccines we know have done a
great job of preventing very young babies from becoming seriously ill, those vaccines actually
don't stop people from picking up the bacteria in their nose, they don't cause disease. So,
in all of the high-income countries that have switched to those vaccines,

(06:01):
we suspect the level of circulating bacteria has grown and grown and grown and are giving
rise to these very significant periodic outbreaks.So, vaccination is critical for saving the lives
of young babies. And unfortunate we've seen eight deaths in the UK since Christmas of this year,
showing it's still a potentially fatal disease, but we're unsure as to the ability of these

(06:25):
new vaccines to continue to control the circulation of the bacteria. And that's
the big question in the field at the moment is, how do we implement control?
Because although we could probably, and in fact many have designed new, improved vaccines,
it's very difficult to implement a new vaccine to replace one that already exists,

(06:45):
particularly for the childhood schedule, where it's crammed, and most vaccines are given as,
say, 5 or 6 in one shot. So, the science is there, the regulatory framework and how to pick apart
and replace, you know, one part of a complex schedule is the big question at the moment.
So, if it's sitting within people, presumably it's evolving as it's sitting there. So,

(07:09):
what's the selection pressures that's going on?So, it's interesting, so, you know, we have
this picture of organisms, and bacteria in particular because they can evolve quickly,
constantly changing and picking up mutations. We don't see any of that with Pertussis.
So, if you compare the range of mutations, the number of mutations, it's what's described

(07:29):
as mono morphic. So, we can sequence, and we have done in fact, hundreds of strains, and we
see a just a handful of mutations between them.So, we're not sure whether that means mutations
don't arise very quickly. So maybe it has a really high level of, you know, editing out these
mutations, or whether the selection is so strong that any mutations that do arise create a fitness

(07:50):
effect, so that they’re quickly outcompeted. But the one thing we do see is that,
in those countries that have switched to these new vaccines, one of those vaccine antigens,
one of the proteins used, is an outer membrane protein, sits on the surface of the bacteria.
And we know from studies that most of the strong immune response is directed against that protein.

(08:12):
And so, in most countries that have switched to those new vaccines, 90% of the strains no longer
express that protein. So, it's clear evidence that there is selection on these bacteria, but,
you know, doesn't fit that all of the selection on these is from vaccines, because actually we
vaccinate mainly babies, and we know that the immune response to those vaccines’ wanes. So,

(08:36):
it's literally gone by the age of about ten.So, part of those studies what we need to do
is to work out, where is the bacterium? The epidemiology doesn't fit with it residing
and circulating solely in young babies. So, who is carrying it? For how long? And what is that
interaction? Because it's an organism, it's a bacterium that is remarkably devoid of the

(08:59):
diversity that we would expect to see in something that's just, as far as we know,
circulating solely within the nose of people.You know, biology 101 suggests you have to
vary in order to constantly circulate amongst the same host, because you would expect them
to build up some level of immunity. So, we think the organism has the ability to
suppress long lasting immune responses. And we would like to work out how it does that.

(09:24):
So, is it something that mainly affects, so we know young babies, is it something that it tends
to affect older people and that kind of, you know, adults generally tend to be okay with it,
or is it something that we all need to be starting to be concerned about?
You've hit the nail on the head. So, if you look at a clinical microbiology textbook,
Whooping cough is a toxin mediated disease of young babies. But actually, if you look at studies

(09:49):
where they've tried to look for evidence of what might be causing chronic cough, and thousands and
thousands of people report to GP's, and hospitals around the world with undiagnosed chronic coughs,
so three weeks or more, is the classic one.In some of those surveys, up to 30% of those
people have evidence of recent Pertussis infection. So, the emerging picture that in

(10:10):
very young babies, are the ones that display the classic symptoms of Whooping cough. So,
this paroxysmal cough with the large intake of breath, because they've been coughing,
i.e. the whoop. But actually, that's probably a feature of a very poorly developed, small
respiratory tract, i.e. babies. In older people, adults, adolescents, it probably

(10:30):
manifests just as a prolonged chronic cough.And certainly, in the outbreak we're seeing
at the moment where there's, you know, over a thousand cases a month, over 50% of those are
in 15-year-olds or older. Most of those is showing as a really annoying, debilitating,
but chronic cough, rather than classic whoop.So, it's almost like it's hiding, isn't it?

(10:51):
Because, you know, a whooping cough and you're, kind of, looking for a certain,
sort of, set of symptoms. But actually, what we're finding is it's manifesting itself in a different
way, in older people. And so, it's clearly traveling and, on the rise, and causing infection.
It is, I think, one of the unknowns there, is whether we've been duped
by the initial description that Pertussis infection was whooping cough, nothing else,

(11:15):
and it happened in babies. And if you don't look for something, you don't find it.
So actually, I think the jury's out on whether it's always infected older people, but without
the classic whoop, or whether this is a newer manifestation. And it's probably actually it will
be a mixture of both. So, I think the more the organism is circulating because of the change in
vaccines, I think probably the more you will see it causing symptomatic infections in older people.

(11:40):
And interestingly enough, it's changed within, you know, just decades it’s undergoing a
metamorphosis. And probably, you know, 3 or 4 different manifestations since we've
started to really, A) track it, and then, B) try and do something about it by vaccinating.
So, is that essentially what you're trying to do? You're trying to track this and sequence it and
see if there's any kind of particular differences that are arising? How are you doing your research?

(12:05):
So, we do use genomics for sequencing, because it's so devoid of clear signals. So,
we can't just focus on a subset of genes and know that we can pick up and we'll be able
to classify lineages, or clards, or things that you can do maybe for say, E. coli or Klebsiella.
We've realized that to be able to give fine scale resolution and to work out

(12:27):
maybe transmission chains or really to identify differences that distinguish strains that were
isolated pre vaccine, or during the different types of vaccine use, we need whole genomes.
Even then the signal that we get is a low level of mutations. And we're still trying
to work out what those mutations actually mean. Do they change the biology in somehow? I think

(12:49):
that loss of Pertactin, so that outer membrane vaccine antigen, there is very clear evidence
now that that gives the organism greater ability to evade vaccine induced immunity.
But there are other certain types of mutations, single changes in bases that have gained almost
mythical status, because the only signal we've had of, for example, that change during the

(13:12):
wholesale vaccine era, but actually you get different results depending on the assays you
tried to look for. So are they more toxic for example, some studies say yes, others say no.
We're limited by tools to really devise assays that are relevant to the symptoms we see in
people, because there is no assay for cough, for example. So, whereas maybe with Staph aureus, they

(13:37):
cause different types of infections, go into the skin, or into the blood, with Pertussis, all of
the clinical data is you get cough, and that's it.So, what does evolution tell us
about Pertussis then?To me it's a really interesting
case for being able to almost do the sort of, time travel experiments. So, the genomics has

(13:57):
told us actually that Pertussis has evolved really very recently, maybe even within the last couple
of thousand years, which evolutionary wise is virtually moments ago, from an ancestor that's
still around today. It's called Bronchiseptica.So, Bronchiseptica is a bacterium that infects the
respiratory tract of pretty much any mammal in which you care to look you will find it,

(14:19):
but it's very rarely a pathogen. So, it's largely just something that it sits in the nose,
it can be carried for the lifetime of an animal, but then transmits to others, but
is perhaps more of a commensal than a pathogen.Pertussis is almost a subset of Bronchiseptica
that's undergone an evolutionary process where actually it's streamlined its genome. So,
it's got rid of maybe 25% of the genome of its ancestor, and in doing so has become exquisitely

(14:46):
adapted to only infecting the nasopharynx, the nose of humans. And it's outcompeted,
so it's eliminated its ancestor from that niche. We no longer really find Bronchiseptica in people.
And so, we're really interested in that process, as an exemplar of evolution,
to really become highly adapted. And of course, what it's done during that adaptation

(15:08):
is it's changed its biology. It's now become a pathogen, maybe it needs to be pathogenic,
i.e. cause disease and symptoms to spread more efficiently. And of course,
the fascinating side of that is it's probably done so in combination with changes in its host.
So many of the acute respiratory pathogens of humans, such as influenza, are really quite new.

(15:31):
So, for most animals they exist in relatively small populations. And so, an organism has to
maybe be carried for a long period of time by that host, keeping that host relatively healthy
and therefore mobile, for it to be able to then encounter a new host for transmission to occur.
If you now pack your host into dense populations with a high replacement, i.e. birth rate, you can

(15:55):
afford to just let rip and be highly pathogenic, outcompete other organisms in your niche. And of
course, you're going to have a constant supply of new hosts, so you can, kind of, not really care
what you do to your host once you've moved on.And so that's the perfect breeding ground for
these highly transmissible, acute diseases, that is a hallmark of humans, Influenza,

(16:17):
and I think Pertussis is one of those, you know, if we can sort of compare Bronchiseptica...
And interestingly, there's another subset, Parapertussis, that's somewhere in between
Pertussis and Bronchiseptica, it's even more recent, it causes Whooping cough, but less often.
You know, we're trying to do studies, look at the three, you know, what do they bind to in the nose

(16:39):
of the different host? How has Pertussis become so much better adapted to the human nasopharynx?
What are the specific interactions that enables it to outcompete? And then the response that it
induces in people, does that give us clues about this evolution of disease from what
was largely a sort of commensal existence?And so, we think we've got a great model

(17:02):
system to do some really sort of nice time travel experiments. Hopefully find
out something useful along the way about could we actually interrupt that process.
Because obviously, if we can stop Pertussis from binding to the nose, it can't establish
infection and therefore can't cause disease.So that's really interesting because yeah,
as you were saying, so it sounds like it's super adapted. So, you're looking at adaption

(17:24):
in bacteria, and in Pertussis it's become super adapted to be able to infect us through
our noses. So, what other bits of bacterial adaptation are you looking at, at the moment?
You know, you could almost say Pertussis has got this new trait,
this ability to cause disease. And I think when we think about bacteria gaining new traits,
we think that they've acquired genes to do so. This is a fascinating example, it's lost genes.

(17:47):
So, we know that the difference between a Pertussis genome and Bronchiseptica,
it's just jettisoned 25% of its genome. Maybe getting rid of things it doesn't need anymore,
because we think Bronchiseptica possibly can also survive in the environment outside of a host,
but it's jumbled its genome to do so.So, it's got largely the same genes as
Bronchiseptica, but got them in different orders in the genome. And we're really

(18:10):
interested in how does that play a role in the ability of a bacteria to generate adaptation,
and whether that's relevant to what's happened.You know, if we focus just in on what's happening
in the respiratory tract, we can do those experiments. We can get respiratory tissues; we
can grow respiratory cells and just actually look at that interaction between the three different
species, and the cells from the different host. And that's what we're doing at the moment, we're

(18:33):
trying to identify patterns of, which molecules from the bacteria bind to what on the host? How
do they differ between them? And then, how just the host cells respond differently to each of
the three species? And does that then set up the consequences that we see, i.e. disease in one,
or benign carriage from another.So, what's next for you?

(18:55):
I think the next big thing, can we get together at a global level and convince funders that what
we need to do is establish exactly where the bacterium is, in the human population, so a
large-scale study of carriage. So can we identify the cohorts that are carrying it.
So, you know, what proportion of people might carry this bacterium at any one

(19:18):
time? Is it particular age groups? How long do they carry it for? What percentage might
even have symptoms? How often do they transmit?Because I think what we do need to really do is to
work out how to use our vaccines effectively. So, this idea of boosters, so in the UK we now offer
a booster shot against Pertussis to pregnant women, because we know that the really young

(19:41):
babies who are too young to start their own vaccinations, are the ones super susceptible
to the fatal disease. But actually, we need to know whether we need to cocoon older people.
So, grandparents have a lot of interactions with young babies. So, do we need to add more
boosters? Will that help curtail the resurgence that we're seeing? But how often can we boost
people and still be effective? And who's going to be the most beneficial groups to receive those

(20:06):
boosters? I think that's a pressing situation that has immediate public health consequence,
but is a remarkably difficult one to implement globally, where it needs to
be done, because we see different patterns of disease in different countries. And who's
going to pay for it is always the big question.Andy, thank you so much for talking with me.

(20:27):
This was a podcast by the Milner Centre for Evolution at the University of Bath.
I'm Turi King and thank you for listening. If you have any thoughts or comments on this
or any other episodes, please contact us via our X channel @MilnerCentre.
For more information about the Milner Centre for Evolution, you can visit our website.