Hello, and thank you for listening to the MicroBinfeed podcast. Here, we will be
discussing topics in microbial bioinformatics. We hope that we can give you some
insights, tips, and tricks along the way. There is so much information we all
know from working in the field, but nobody writes it down. There is no manual,
and it's assumed you'll pick it up. We hope to fill in a few of these gaps. My
co-hosts are Dr. Nabil Ali Khan and Dr. Andrew Page. I am Dr. Lee Katz. Both
Andrew and Nabil work in the Quadram Institute in Norwich, UK, where they work
on microbes in food and the impact on human health. I work at Centers for
Disease Control and Prevention and am an adjunct member at the University of
Georgia in the U.S. Hello and welcome to the Microbial Bioinformatics podcast.
Andrew and I are your co-hosts today, and we're continuing our series where we
examine a particular microbial species in some depth. Today we're talking about
Mycobacterium tuberculosis, and we're hoping we can discuss some of the specific
issues for bioinformaticians to keep in mind when studying this organism. We
have a number of special guests on the show today. We are joined by Dr. Susie
Hingley-Wilson, who is a lecturer in bacteriology at the University of Surrey.
She works on tuberculosis, and in her lab they focus on its survival and
persistence. We have Danny Best joining us as well, who is a senior lecturer in
microbial metabolism at the University of Surrey. She is a bacterial dietician,
so she's interested in what MTB actually eats. And we're also joined by Dr.
Connor Meehan, who is an assistant professor in molecular microbiology at the
University of Bradford. He specializes in whole genome sequencing and molecular
epidemiology of pathogens, primarily Mycobacterium tuberculosis and genome-based
bacterial taxonomy. So Andrew, do you want to kick us off? Yeah, so when people
think of MTB, their mind usually wanders back into history to the consumption
and, you know, the time of Angela's ashes. So is TB still a problem these days,
and why should we be concerned? Well, yes, TB is still very much a problem, and
in fact, until last year, TB was actually Mycobacterium tuberculosis was
actually the leading cause of infectious death. It overtook HIV. So aside from
the COVID pandemic, it's still a really, really important pathogen. And there's
no doubt that, you know, when the COVID pandemic has been long, you know, got
under control with all the multiple vaccines that have been developed, that TB
will continue to be a problem. And actually, in the TB community, we've kind of
looked on awe at the speed at which they've come up with COVID-19 vaccines. And
we're still running with a vaccine that is, is it 100 and 150 years old? So
yeah, very much so a problem. So does that mean the BCG vaccine is so good that
it's worked for 150 years, or it's antiquated and we need new treatments? The
BCG vaccine is incredibly complicated, because whether it works or not, is very
dependent on where you live in the world. So the closer you live to the equator,
the worse the BCG vaccine is. And the reason that this is, is that they think
that people who live nearer the equator are exposed to environmental
Mycobacteria, and that this sort of means that their immune system have kind of
been primed. And so when they're vaccinated, they don't get a proper response to
BCG. However, BCG is very good in protecting children from TB and from
disseminated disease. Let's be honest, BCG has been the most widely, it must be
one of the safest vaccines, right? It's been given to the most people in the
world. It's very, very complicated and it's, you know, to do with the
individual, where they live. And, you know, in some individuals, it does have a
lifelong protection, but it's very variable. And in some places in the world,
they found the protective efficacy can be less than 5%. But we do have
antibiotics. It is a bacterium which responds to them. So, you know, why are we
still concerned about it? There's approximately one and a half million deaths
every year from TB. And about 80% of those are due to fully drug sensitive
tuberculosis cases. So even with the drug resistance, which is a huge problem,
that there's still a huge problem there, not counting for the drug resistant
strains. So treatment takes, for a drug sensitive, it's four drugs for six
months. And so you have a problem with adherence in some cases, you know,
because symptoms will go away after a couple of weeks. Actually, your bacterial
load goes down to almost non-detectable after a couple of days. So when you have
six months of four different drugs that you have to take, even if it's
sensitive, you can have problems with supply, you can have problems with
adherence, but also just with efficacy. We don't always know exactly how all the
drugs interact with each other. We don't know exactly how they all work. So some
of the drugs that we have for a long time, we don't even know how they actually
work properly. And then that's not until you get into the drug resistance and
that's a rising problem for sure. So about 10 million cases of TB every year and
about 500 to 600,000 of them are drug resistant. So the vast majority is still
drug sensitive related, but you have access problems. You know, most TB cases
are in countries that don't have great health care systems. Myself and Andrew
can think about it from Ireland. There was a lot of TB cases in Ireland for a
very long time. And now people say, where did it go away? We got better health
care. People didn't have to all live, 20 people to a house. People were able to
just have better immune systems. And TB is a public health problem that's
related to poverty a lot of the time. On the negative side, there's no doubt
that COVID will have a massive impact on people getting TB treatment. And
there's already some documented evidence that people aren't either getting
diagnosed with their TB and then they're not carrying on with their treatment.
So that will have a massive knockout effect. But there have been some hopeful
things. So, for example, there's now a six month new treatment for drug
resistant TB, whereas before you had to treat for 18 months to two years. And
they've also, I just saw that there's been a new clinical trial where they've
reduced the treatment time from six months to four months. So there are some
hopeful signs on the drug market. But when they last looked at TB pre-COVID, the
WHO's sort of goal to end TB is not on target. They are managing to reduce the
incidence of TB. They've massively reduced the death rate, but they aren't able
to significantly chink into that incidence. And I think that that's where COVID
is going to have a really serious impact. I read somewhere that about one third
of the world has latent TB. I think it's one quarter now. I think, well, yeah,
it depends on who you ask. The newer numbers say that that seems like a massive
overestimation, but it's definitely more than people think. So that's a lot.
That's a big number. The R0 of TB is about two and a half. So the R number is
everyone here is now for COVID. So it's about the same as COVID, but that's only
of symptomatic people that we know of. So we know that one TB patient will
infect on average two to three people who will become symptomatic. So the
calculation was that actually it seemed that it was up to 10 people that would
be there and be asymptomatic. And then they extrapolated from that the number of
people that have it to the number of people that could have it. And you come up
with about a quarter. But obviously, it's also localized. That doesn't mean that
loads of people in countries without TB have it. But it does mean that you
probably have a lot of latent period and a lot of asymptomatic people in high
burden countries, South Africa, China, India, these kind of countries. And what
also factors into that is on average, it's about one year after being infected
before you see symptoms. Some people, it can be two, it can be 10, it can be
longer. So mycobacteria are just really slow growing and slow to present. So
it's about like you have asymptomatic people, but then you have latent people.
This is not the same. And you've subclinical and you've clinical. So it's it's
pretty complicated that way. Can I ask, has there been any studies done with
genomics looking at, say, when a person is first infected and then it goes into
the latent stage? And then what does their genome look like? 10, 15 years later,
whatever period of time, you know, how has it evolved within the host? Is it the
same? Is it quite different? Some studies have started doing that. There was a
thought that when it was in the latent period, its mutation rate was
significantly slower than when it was in the active period. That doesn't seem to
be the case. But you're thinking, yeah, so mycobacterium tuberculosis has a very
low mutation rate anyway. It's about 10 to the minus 6, 10 to the minus 7. So it
doesn't evolve very quickly over time anyway. We can probably get into sniff
distances between people. It's not always known because it's unlikely that you
would have the genome when the person gets infected and then also have the
genome 15 years later. Now, we do have them on treatment, but then we also don't
know how much the mutation rate is speeding up due to the treatment pressures
that are there. It's kind of the million dollar question as well, because TB
grows really slowly. And usually you like mutation rate is the dogma is it's
affected by growth rate. But when you look, it looks like TB evolves more.
Although it's slow, it looks like it evolves.  more than it should. So I think a
fundamental question that still hasn't been answered, which I think is quite
intriguing, what's driving that? Is there some sort of clock-like fashion? Is it
to do with growth rate or are there some sort of mutators within the host? I
don't think that's fully, to me that's a fundamental scientific question that
still remains unanswered, which I think is quite interesting. There's another
complicating factor as well is with mixed infections, isn't it, as well? So we
had patients that had sort of a multi-drug resistant and a non-drug resistant in
the same lung. So you've also got this other issue, another complication that
can happen there as well. What happened at the same time they got infected or
were they infected at two different time points? Like was it a cloud of mixed
infections or was it...? So this was an interesting case actually. There was one
strain was sequenced, one came up, so what happens is when it's diagnosed, it's
the fastest growing which will be diagnosed, and then another strain, the
patient came back again, there's another strain after sort of two months that
had taken over and this was an isoniazid, like a first, a frontline drug
resistant strain, and there were two completely different strains that, you
know, this had done, this, the faster growing strain, which was a non-drug
resistant, was there, and then once the patient took treatment, the other strain
came up, and mixed infections are really massively underdiagnosed in TB because
it's the fastest growing strain which grows first. TB is coming along on the
genomics, but when I meet people who work in E. coli and salmonella, they're
just like, oh, that's what you're doing? You don't understand that? It's just,
there's a lot of things that bacterial epidemiology or geneticists really think
is a fundamental thing that you would know, and in TB we don't know so much. So
for a very long time it really was, they had one strain, that strain was
everywhere in their lung or whatever, and then they passed that one strain on to
another. Now we're seeing that when we are doing the deep sequencing, we're
seeing a lot more within host diversity, so we're seeing that the cavity that
sometimes is in the lung might have a different subpopulation to what would be
in the rest of the lung, or if it is, and then what we actually see in the
sputum, so what they cough up in order to give us a sample, is not always
representative of what's even in the lung underneath, and this is because of a
lot of different things. Different drugs penetrate into different parts of the
lung, creating different types of pressures on treatment, and indeed we don't
know that much about the transmission of multiple strains to people, or whether
we have one that's, that is transmitted. So all of this is very, very new, and
Naki Kamos is showing a lot of this. I'm trying to show a lot of it, but we're
not getting the funding for it, and other people who are better are doing it.
But it's, deep sequencing is really difficult with TB, because we have to
culture it, we have to culture for eight weeks. As Suzy just said, one strain
will take over because it's faster growing. Some lineages grow faster than
others, because we don't even know what to put in for proper growth of some of
the lineages, and so now we're trying to go to that direct from sputum
sequencing to try to get us a better picture, but that's really, really
difficult as well. Do you believe that this intra-host variation is going to
change the sort of dogma around MTB, where, I mean, the main thing you know
about MTB is like, it doesn't have any sign of recombination in the genome. So
there's no sign of recombination, and even when you look at these, there's no
recombination going on. This is because of a couple of different factors. The
cell wall is covered in these mycolic acids and other things. Naked DNA doesn't
seem to be going in and out. We don't know that much about the phages, but it's
just all the different ways that recombination can occur, doesn't seem to happen
within classic mycobacterium tuberculosis. Mycobacterium kineti, which is
extremely closely related, lots of recombination occurs there. But a lot of
papers have shown that even though you have mixed infections, they're not
interacting with each other in the same way that you would think of like with
viral recombination. They're just both present and seem to then result in worse
clinical outcome. So they're essentially mutually exclusive. One would fight the
other one out. Is that the case or we don't know? Maybe. They're just, they're
not recombining their genomes and that's as far as we can say, I guess. It could
be a localisation. Things like this in the lung, the different foci of infection
are normally very local. So there'll be lots of, one sort of population in one,
one sort of virgin in the other. So you've got this distance between them, if
you will, as well. Yeah. I mean, some groups are doing in America, some groups
are doing some really exciting experiments where they actually barcode different
strains and sort of compete them and see where they go in the granuloma and that
heterogeneity. I mean, that's the kind of thing about TB, whatever it does, it's
going to be terribly heterogeneous. So that showing that actually one type of
strain may survive better in one lesion and the other type might survive better
in another lesion because the lesions are so heterogeneous. But one thing I
think is really interesting, only because I've just read a MSC project from
someone in South Africa, is people starting to look at all the DNA repair
systems and the effect that has, like the error-prone DNA repair systems and the
effect that might have. And actually, you know, you have those systems which
kind of create that noise, which allows the genome to mutate more and actually
gives the strains advantages. And I wonder if that kind of might explain a bit
of the puzzle about the mutation rate with TB. I mean, I don't know a lot about
it, but it kind of piqued my interest. I thought it was quite interesting. And
that might change the cell types there as well. So if you've got different
strains, you'd have different cell types there with, say, more macrophages
affecting it or more B cells in another might have, you know, that point you've
got, it's just sort of increasing the heterogeneity even more, isn't it, with
different strains? So a lot of what was taught about TB, Mycobacterium
tuberculosis, if you ask somebody 15 years ago who was doing genetics, they'd be
like, oh, well, it's kind of boring for a bacteria. There was really this thing
that it's strictly clonal. There's not really any difference between the
lineages apart from extreme, specifically known regions of difference. It's just
one strain going from one person to the other. And every single new thing that
comes out that's showing more genomes, it's just creating a more complicated
picture. So we keep on trying to, if we go to bioinformatics side, we keep on
trying to say, well, this is the pipeline we're going to use. And then another
paper comes out going, that's just not going to work because there's this
diversity or there's this issue or it's selection bias or all these different
things. So it's just called an evolving field as an understatement. I just
wanted to clarify. So there's no known or canonical mobile genetic elements at
play here or? Not in Mycobacterium tuberculosis, single chromosome sitting by
itself. Even the Mycobacteria in general don't have a lot of plasmids, but most
of the other opportunistic pathogens do. But maybe we get where you're going
with that in terms of drug resistance and stuff like that. It's chromosomal,
it's mutations related or potentially epigenetic, but there's no there's no
plasmid or anything that's causing this. Are you able to do hybrid capture on TB
and could we come up with a scheme where, you know, you pull down from a from a
sample that's hasn't been cultured all the TB and then sequence that population
of diversity really deeply? Right. So, yeah, we just had the European Society of
Mycobacteriology conference and this was talked about a little bit by Gallo
Goig, who works in Switzerland, and again with the NACICOMAS. The difficulty, so
yes, hybrid capture has begun to work with sure select and things like that.
It's based on the H37RV genome, which is our reference genome, which is lineage
four. And it does seem to work to a certain extent. It's expensive. And that's
why we're still working on trying to make it cheaper, because when we're looking
at doing that for epidemiology or drug resistance, we want to start doing it in
high burden countries. Yes, we can do it here in the UK, four and a half
thousand cases a year can probably handle that. But most countries, we want to
be able to get the sample numbers up and we're talking the number of COVID cases
we see this year. That's what they're seeing every year with TB, right? So think
of all the things that have gone into the COVID resources we have for just this
one year. They're doing that every year. So hybrid selection does work to a
certain extent. We have a couple of different problems. Getting the DNA out is
very difficult because of the waxy cell wall. Normal sonication just ends up
breaking up all the DNA into very short fragments. So we have to do work a
little bit better with that. But yes, hybrid capture is working a little bit
better with it, assuming that the gene content is the same in all of them. But
in some lineages, the gene content is different. So we found in lineage five,
that there are certain genes in some of those strains that are not in H37RV. So
then they wouldn't be captured right from there. So it's getting there. Again,
like hybrid capture, the papers came out this year and last year. So it's still
very, very new and trying to go towards that, but in an affordable way, because
what's important in TB is that we don't create a two tier system. We don't have
all these technologies that then go into something that's only in high income
countries, where the reality is that we're here to try to help people in high
burden countries. And these two only overlap in one country, which is China. So
I suppose the reason I bring up hybrid capture, maybe this is just a random
crazy rabbit hole. In Oxford for COVID work, Tanya Gubilek did a lovely paper
where they were looking at the population of diversity within one host, and then
like all the people that they would have infected.  so they could have these
chains of transmission and they could see that in some cases, minority variants
are being passed on. And I was wondering, could you, if you had those chains of
transmission, say within a population, could you track how often you get like a
cloud infection being passed on or, you know, a mutation being passed from one
person to another, you know, is this something we can possibly capture really
deep sequencing using hybrid capture of MTV? In theory, yes. Write a grant
there, Connor. Other people have already written that grant, so I'm not going to
compete with them. But from what I've seen, I'm trying to remember what's
published and what's unpublished and what I can say and what's not. From the
published literature, we do know that there are some minority variants that are
being transferred. Some people have shown that it's the same two or three
strains that were in transmission clusters going across people. So we do know
that it's not just one thing being transferred and that's even from culture base
where you do deep sequencing. So I think it's going in that direction that we'll
see more of this. A question that we really are asking at the moment is how much
is being transmitted between the different people? And is there a selection on
that? So I think back to HIV that I used to work on, the dominant strain inside
the patient was not always the dominant one that was being transmitted. So the
fitness, what fitness means in TB is very different because transmission fitness
versus obviously culture fitness and everything. So I think we're going towards
that. But you also remember that when a patient coughs up sputum, there's not a
lot of TB in that sputum. So we just don't have a lot of cells to work with when
we do all of this. It's not like a lot of other things where you take a blood
sample and it's just filled with bacterial cells in there. So we just don't have
a lot of starting material when we don't culture first. So kind of, excuse my
ignorance, but going back to HIV, right? I recall in HIV research, when they do
genome sequence, they want to see what all the minority variants are and what
percentages are in the sample so that then they can say switch drugs. So if a
drug-resistant mutation is popping up, is that something they do in TB or is it
just whichever one goes fastest, that's what we treat with and that's it? So in
the UK now they're using deep sequencing to look for the SNPs. But the
difficulty with that approach is obviously they're only going to see the SNPs
that they are known to be associated with drug resistance. And I noticed that
the WHO just released a list actually of all the different SNPs that are
associated with different drug resistance. So yes, in the UK that's done.
Elsewhere, it will be what they mostly look for is because in TB it tends that
you get isoniazid resistance first and then the other resistance tends to
follow, there's different quick and dirty methods to look for that resistance.
But it is a massive challenge in TB because obviously you've got a combinatorial
problem. If you're giving somebody four drugs, it's what do you take out and
what do you put in and then how do those drugs interact with each other? But
with this new, I think it's called BPAL, is it? It's called a BPAL, the new
treatment for drug-resistant TB. They can then say, right, we've got an
isoniazid resistance strain or a rifampicin resistance strain. We can convert
them onto this regimen for drug resistance. But the key in resource-limited
countries is you just want something quick and dirty. So in a way you don't want
all this finesse because you haven't got the time or the money. The person may
have walked 20 miles to get to the health service. So you haven't really got
that kind of wriggle room that you've got in the UK to kind of dig down. So only
two countries use genome sequencing for drug resistance determination in the
world, which is the UK and the Netherlands. I think New York use it for their
local public one. At the moment, let's say you were in South Africa and you came
in, you would have a sputum sample taken. They would then put it onto an expert
machine, so a gene expert machine that tests whether it is TB and will tell you
whether it's resistant to rifampicin. So even though isoniazid resistance comes
first, they mainly test for rifampicin in the clinic. If the person is resistant
to rifampicin, they go onto multi-drug resistant treatment, normally without
checking the other drugs even work. Then they're put on the MDR one. Then you
want to know whether they're resistant to fluoroquinolones. If they are, then
they have to go onto what used to be called an XDR treatment, but all of these
terms have changed in the last three years. Actually, the XDR one has changed in
the last two months, maybe one month because of the way we've changed, the way
we treat multi-drug resistance. So it's different for a lot of other things that
people are used to, where they're used to take the sample, get the genome,
decide on things from there. With TB, even doing that here in the UK, it's get
the sample, wait three weeks, and then get the SNPs and then go off. So they'll
normally, that's how long, you can maybe grow it in a week in order to get
enough to tell you the majority SNPs that are there, but these minority ones,
we're still very reliant on the culture and we're working hard to moving away
from culture, but that's just, it's really, really difficult to do. And moving
away from culture would be fantastic for a lot of other places. Then you
wouldn't need a category two or category three lab and all that. And there is
deep sequencing, target sequencing of the drug resistance related genes that you
can do directly from a sputum sample in what's called a deplex machine. And that
does 30 something genes and that'll tell you your resistances without having to
grow it all up. But as Danny said, it's based on knowing those exact SNPs. And
we get that for rifampicin and isoniazid, we do pretty well up in the 90%
sensitivity and specificity that starts to drop off for a lot of the new ones,
but Daquan, which is kind of seen as one of the new key drugs that we're using,
we're still pretty shaky on how well we do with those SNPs. And that's, it's
about how the resistance comes about in those ones. So it's still pretty
complicated on that side. So I just wanted to clarify when you're talking about
these resistant SNPs, despite this being quite slow, you always see new variants
that confer resistance or? So let me take two examples for you. We have
rifampicin, which is mutations in the RPOB gene primarily in an 81 base pair
region, confers 95 to 98% of rifampicin resistance that we see. And the gene
expert essentially works on that 81 base pair region. It's got probes. It does a
quick PCR against those probes. And then it says, if it binds, it's a wild type
probe, there's no resistance. If one of them doesn't bind, you have resistance.
So rifampicin is very, very concentrated in one area with very known SNPs coming
up over and over and over. For pyrazinamide, it's in PNCA in the gene. It's a
product that's then converted by PNCA into the drug. And their variation appears
all over the gene. And it's much more difficult to say. And bedaquiline is the
same. We see new variations coming up all the time with that. So it really
depends on the drug and it seems to relate to how essential the gene is as well.
So for some of them, we do super well. Thoracrinolones, rifampicin, and
isoniazid, almost always the same resistance. Interestingly for isoniazid, it's
almost always exactly the same SNP and exactly the same gene. But in the lab,
when you try to artificially get it to do it, it almost never will do that
resistance SNP. So it's just some other pressures that are there with that. I
did just want to mention with pyrazinamide, you've got some species that cause
tuberculosis that are inherently resistant to pyrazinamide as well, like
Mycobacterium bovis. So then you've got, you know, that there's sort of a deeper
problem there as well. Hopefully we can get a better vaccine too. Now we know
how fast it can be done with COVID. Near where I grew up, there was an old
hospital, which was like a TB quarantine hospital. You know, long ago, back in
the day, that's where they shoved people when they couldn't treat them. So are
we going to go back to those kinds of days, you know, with totally drug-
resistant TB, where we're just going to have to lock people up? I think we have
in some cases. Some cases there's strains that are completely resistant to all
known drugs. So we've gone back to surgically resecting lungs, so taking out an
area of the lung that has caused TB. I mean, that happens already with extremely
drug-resistant strains, yeah. And so what is the categorization? So you have
MDR, multi-drug-resistant, and XDR, extensively drug-resistant. And then kind of
what's the next level above that? I remember there's like a New Delhi strain,
but of course we're not meant to be calling things after places. In theory, you
have TDR, totally drug-resistant after that. The main levels we use are RRTB,
rifampicin-resistant TB, MDR-TB, which is multi-drug-resistant TB, resistant to
rifampicin and isoniazid. Pre-XDR is fluoroquinolone. Fluoroquinolone's by
itself, but no other ones apart from MDR. And then XDR used to be
fluoroquinolone and an injectable. We don't really use injectables as much
anymore. Now it's fluoroquinolone plus a category A drug, which at the moment is
just bedaclin or linoisilid. But they've said category A so that other drugs can
be added into that if we do. And they're essentially the core drugs for treating
MDR-TB. So it's saying XDR-TB is now, you're resistant to at least two of the
three core drugs for MDR-TB treatment, until they potentially move
fluoroquinolone to first line, but that's a completely different discussion. And
these get more and more toxic as you go along, don't they, as well? As you go
along this system, they're incredibly toxic drugs.  cost for people in low-
income countries? In high-income countries like us it's covered, in low-income
countries yeah not so much. That's obviously an issue and it's probably going to
be an issue. It was one of the criticisms of, I think they've recently developed
a more child-friendly set of regimen and one of the criticisms was the cost
because I think the new regimen for MDR-TB is likely to be quite costly for low-
income countries. It's quite interesting that one of the drugs that they trialed
that worked, linazolid, which I can't say very well, the history of that is that
basically it defies all science because basically a clinician was so desperate
to treat TB patients with something he just shoved in linazolid into the regime
and it worked which is quite amazing if you think about you know all these fancy
trials and all this kind of you know hypothesis driven yes and then and then he
just tried it and and it worked so that's kind of how desperate people who are
actually at the coalface are. You know if you watch they made an incredible
documentary about drug-resistant TB and as Suzy was saying well it's totally
drug-resistant TB people have to go off and die on their own and it's not a fast
death it's a slow horrible death and they had this documentary I can't remember
what it was called where they had this young teenager who was just in an empty
house just waiting to die of asphyxiation effectively which is is fairly you
know in in 2021 that we've got a disease which was one of the first diseases to
be described first infectious diseases to be described by Robert Koch that we
still haven't managed to to you know cure that people are going away I mean to
me I still even though I work on TB I find that fairly shocking and you know
when we look at COVID I know I keep banging on about it but my line manager said
that each one of the approaches used to make COVID vaccines have been proposed
for TB but there's been no money behind it right because the vast majority of
people who get TB are in resource limited countries so there is no country that
is free of TB and TB is a pandemic and will continue to be a pandemic and when
you see the difference of the response when you get high-income countries
affected as a TB researcher you'll you'll kind of you know you don't even know
what the what co-infection is going to be like with them with COVID as well I
mean that's people getting long COVID you're going to get and we're going to get
even you know it's going to get even worse it's not going to get better so maybe
that's another grant you can put in to uh investigate that because all the
research funding seems to have been re-diverted to COVID so new drug development
is really slow we only have bedaclin and now technically lanazuli come up
recently just because it's intrinsically resistant to a lot of things beta-
lactamases and all that it's just they can't get into the cell because of this
waxy cell wall what's interesting is I think it's going to start going in the
phage route of maybe trying to see if we there are phages that can do it and
what I'm actually interested in kind of what is what kind of Danny works on of
can we starve it out in other ways can we just cut off its sources of nutrition
and other things and try to try to use alternative non-antibiotic ways to get
rid of TB that's something I'm trying to pursue in the lab is and something
that's quite sexy at the moment is adjuvant therapies therapies that will make
the the drugs we have now last longer I think that is kind of what we need to do
probably for all infectious diseases right because you know there's there's no
money in antibiotics because as soon as they get produced the bacteria get
resistant to them so we need to find strategies to make the drugs we have last
longer are people co-infected with other pathogens and is TB like the
opportunistic pathogen that will finish someone off or is it that TB is the
primary driver of all of this disease so well if you if you think about TB and
HIV they form a really unholy alliance because TB basically makes HIV worse and
HIV makes TB worse and I used to live in in Malawi in the 90s in the absolute
height of the HIV I mean it was it was like 30 percent of women attending
antenatal classes were HIV positive all of those HIV patients died of TB so from
that point of view from other infections it's it's interesting too like there's
a lot of cross between parasitic infections but that's more complicated some of
them seem to actually provide some form of protection from TB and some of them
may make the TB worse when they've looked into that there's then from non-
infectious diseases diabetes is a massive risk factor for TB so and a lot of
reactivation as well will happen so exactly what Dan is saying you'll get you
know with onset of diabetes if you've got a latent TB infection which a quarter
of the world's population do that will then be reactivated by diabetes
reactivated by HIV possibly reactivated by COVID but we you know we don't know
yeah that's going to be terrifying all right so that's all the time we have for
today this is part of our ongoing series to talk deeply about a particular
microbe and this time around we had mycobacterium tuberculosis I want to thank
our guests Drs Suzy Danny and Connor for joining us today and I'll see you all
next time on the Microbinfy podcast thank you so much for listening to us at
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