Lecture 15- spirochaetales Flashcards
Key Questions
So the key questions, what are the unusual characteristics of these organisms?
Um, they’re quite understudied, actually. They’re quite surprisingly understudied.
And there’s a variety of reasons for that. What are the common features of these diseases?
So they’re often diseases, uh, associated with stealth, um, and particularly syphilis.
Why is it known as a stealth pathogen? And, um, why you really don’t want to get Borrelia burgdorferi infection and leptospirosis, which, uh,
probably many of you may have not heard of, is one of the most neglected diseases and one of the commonest zoonosis.
Um, so, again, uh, commonly occurs more frequently in poorer countries.
So we tend to hear less about it.
SPIROCHAETALES: PHYLOGENY
So this is the phylogeny of, um, the different groups of spirochaetes.
And there are four clinically important genera.
the treponema, borrelia, leptospira and brachyspira.
we will not discuss the brachyspira, which is a pig pathogen
we’re really going to focus on the human pathogens, um, in this lecture.
Characteristics
spirochaetes have this internal periplasmic flagellum.
they’re very unusual gram negative organisms.
And as I said, they can swim through very viscous material.
And this is really, um, important in their pathogenic process.
It means they can swim through connective tissue. And they’ve been very challenging to grow, um, in the lab.
So not, uh, just having animal models.
Actually, we have animal models, but you can’t actually grow them.
Um, either can’t grow them or can’t grow them well, in vitro.
And this really impedes research into these organisms.
GENERAL SHAPES OF SPIROCHAETALES
they’re sort of classified by the number of spirals.
So here you can see, treponema, leptospira and Borrelia.
Uh, so they have this really unusual coiled, um, shape of bacteria,
and there’s lots of them that are actually, if you took a scraping from inside your mouth and,
um, looked under a microscope, you’d probably see some organisms from this family so they can live in your, uh, oral cavity.
Cranial trephanation
Um, and the word trypanon means borer.
So back in the day it was a treatment for all sorts of conditions.
they would quite literally drill a hole in somebody’s head.
Um, which is rather a dramatic approach, um, to treatment.
Pyromania and fighting fire with fire
Wagner von Jauregg
He actually won the Nobel Prize because what he did was he treated syphilis successfully by giving the patients malaria.
and it was a really effective treatment for syphilis.
And then obviously, you had to make sure that the patient then didn’t die of malaria by giving them quinine.
Now, can anybody think how that might have killed the organism?
So anybody what happens to you when you have malaria? I’ve had malaria
Infects the red blood cells.
What’s the classic symptoms Of malaria.
Okay. You get a really, really, really high temperature
A really high temperature. So what do you think’s killing the spirochaetes
What do you think they might be sensitive to? Yeah, they’re very sensitive to high temperature.
So basically what he did was he raised the temperature of the patients, and this killed the spirochaetes.
It’s quite clever, really. I mean, they didn’t have any drugs to treat.
It is quite an ingenious way
If you get malaria. Well, when I have malaria, I was like, literally 40 degrees and I was sitting shivering.
You get this incredible spiking fever.
And because the parasites, are cyclical, they have these cyclical waves.
You then feel marvellous again and think there’s nothing wrong with you, and then you get this fever again.
Treponema pallidum
One SPECIES different diseases and epidemiology
Non-sexually transmitted disease of the skin and flesh
so they’re very sensitive to hot temperatures.
So Treponema pallidum is the species that actually causes syphilis.
But interestingly, there’s lots of subspecies which cause these very endemic diseases.
So Treponema pallidum and all its subspaces are incredibly genetically similar, but they cause these incredibly different diseases that are very defined to particular geographical regions.
So Yaws which is the Treponema pallidum subspecies pertenue is very restricted to Africa, Asia and western Pacific.
And as you can see is that you can get these very disfigured lesions on the face and on the body.
Pinta Treponema pallidum subspecies Carateum is found in Mexico and Central and South America.
And this is very much limited to the skin. and then the third one is Bejel Treponema pallidum Endemicum
again, you get these horrible skin lesions.
And this is in the East Mediterranean, West Africa.
And these diseases are really poorly understood because they’re very
graphically constrained, and they’re caused by an organism that looks just like syphilis.
And what they think is, it’s very much to do with the predisposition of the individuals that are living in that area.
So some sort of genetic component has allowed this disease, these very particular diseases to develop,
but they don’t really understand it because there’s not a lot of people working on it.
But you can imagine for the people that end up having these diseases, it’s quite, you know, stigmatising.
Um, and often people don’t come for treatment because, you know, they’re so ashamed that they’ve got these sort of disfiguring lesions.
But yeah, there’s not a lot of work and not a lot of understanding of these diseases.
species, diseases, transmission and sympotoms
So again, um, my chart here. Um, so.
What I would recommend that you do is have a little bit of time is just having a go at summarising the key differences.
So what I didn’t go through with the three other diseases is how they are treated,
and they are also treated quite effectively by antibiotics.
I mean, the real issue with these, diseases is that patients may not come for diagnosis or they may not be diagnosed when they already have quite a lot of deformities.
And so that can be a problem. But they are treated, um, Bejel is treated by IM penicillin.
Um, and also can be treated with oral azithromycin
Yaws and Pinta can also be treated with azithromycin and wherever possible You don’t want to use I.V. or IM antibiotics because obviously in a low resource setting that creates an additional cost and requires additional expertise.
Sexually transmitted syphilis: Treponema pallidum sub sp pallidum
moving on, really, to the disease of Treponema pallidum that we know most about, and that’s syphilis.
and this is subspaces Pallidum.
And. Yeah, the this bacteria is incredibly fragile.
Um, it’s destroyed rapidly outside of the body.
So that tells you how it has to be transmitted.
It’s transmitted sexually or it can be transmitted from mother to child.
It cannot be spread through environmental means because it just doesn’t survive outside of the body, um, outside of warm mucous membranes.
So it’s a very fragile, um, organism.
How did people study the stages of disease?
And these are the stages of, um, syphilis.
So the thing about this disease is it can lay very silent and very indolent.
Um, if you don’t notice that you have primary syphilis or secondary syphilis, then this disease can remain latent for decades.
And indeed, sort of ten years ago, 20 years ago, a lot of the cases of what people thought were dementia was actually tertiary syphilis.
So it’s a kind of really weird disease. And again, we don’t really understand how it manages to stay in the body.
Um, so sort of silent for so long. So primary syphilis.
You classically get this chancre this syphilitic chancre, characterised in picture A
You can get this in the mouth as well.
But lots of people either don’t get it or don’t realise they’ve got it.
and in babies as well, it can be quite difficult to diagnose however so after 9-90 days you get a primary chancre, So it’s got quite a variable incubation period,
but when it comes to secondary syphilis it can take 4 to 10 weeks, which is characterised by some sort of rash.
but again, you don’t always get this.
Uand then you can get this latent period which can last for years.
It can last for decades. And 30% of patients with latent disease will get benign guma.
and 40% can progress to tertiary syphilis, which is really when you get brain symptoms.
So the signs and symptoms can be as If the patient has mental health problems, dementia so really, really serious condition.
but we don’t understand this latent period the pathogen can go through.
So how did we find out about these stages of disease.
Right. Because if you think about it, you know, you’ve got a patient, um,
who’s going to get this primary disease and then may go years before they get tertiary syphilis.
SYPHILIS: THE TUSKEGEE “to death” STUDY
And this is a really horrible story. Um, because basically, um, in America, there was this famous study, um, called the Tuskegee to death study and in America there’s a large amount of racism.
and so basically what this study involved was recruiting, black people,
black men 600 of them with syphilis, 300 of them without syphilis.
and involved basically saying to them, if you enrol in this study, we’ll give you free medical examinations, free males, free burial service.
But you have to keep coming, to have our assessment.
So there was no informed consent. And indeed, this study changed the whole of the way that we do clinical trials.
There’s still in my opinion a lot of problems in that area, but there is an issue with informed consent.
So basically and this starting went on till 1972.
So some of these people died, right?
So they had syphilis and it lasted to when they had a real treatment for this disease but they did not treat these people.
And they went on, they gave it to their family. and they wanted to study the course of the disease.
And if you read up about this study, there were many whistleblowers who said, this has to stop
This is not our right. Uh, but as I said, it went on for 40 years with these poor individuals, and I think it resulted in a massive lawsuit.
but that’s how they learned about the stages of syphilis.
The non-culturable becomes cultivatable
So one of the issues with T. pallidum is that they are very, very difficult to study because they’re only found in primates and rabbits and hares.
Right. And humans.
Um, so obviously that means that we have some animal models, but they’ve also proved until recently, almost impossible to cultivate.
But this has changed. Um, I was really excited to.
This is fairly new, right, in the last few years.
Well, 2017 they were able to grow T. pallidum alongside rabbit cells.
So it’s called Co-Culture of Cells. It’s quite a complicated procedure
and so a current project is to take this model and turn it into a completely in vitro model.
So get rid of the rabbit cells.
So this is kind of really exciting because obviously when you can’t grow an organism in culture, it limits the genetics you can do on it.
Um, it limits studying its basic biology and not really thwarts, developments in understanding pathogens.
reemergence of syphilis
So like gonorrhoea, syphilis has undergone a complete rebound.
And this is absolutely terrifying. We now have rates of syphilis that have gone up to the same rates as we had in the 1950s.
Um, so here you can say highest for 75 years in England last year.
and also coinciding with this a resurgence of congenital syphilis,
which is also highly problematic and can result in early death of babies
And again, they don’t fully understand why it’s resurged, but there’s certain, you know it could be linked to a bounce back after Covid and changes in sexual behaviour.
They don’t really properly understand it, but it’s obviously quite an issue.
Um, particularly when you’ve got a disease that can go on, you know, and have such a protracted sequelae.
LYME DISEASE/BORRELIOSIS
now the second really important disease, um, is Lyme disease or Borreliosis.
and this we do have quite some incidence of in the UK it’s caused by um Borrelia burgdorferi.
Um, and it’s transmitted by a tick.
Has anybody have been bitten by a tick? Yeah.
Uh, I have never been bitten by a tick, but, yes, I think it’s quite common.
So in the Forest, there are lots of texts that live on deer.
So this is the common sort of area that you might get Lyme disease.
And you get there’s about 85,000 cases in Europe.
And it’s a huge problem in America. And, uh, you get there’s Borrelia burgdorferi stricto, which is only in North America.
And there are also a couple of new species that have been, um, identified more recently.
And it is a particular risk factor if you’re an outdoorsy type person.
Um, so if you’re a gamekeeper a ranger and obviously if you like camping and hiking, um, and this is just to show the Ixodus tick here.
So what that they can look like
LYME DISEASE/BORRELOSIS: Stages of Disease
they actually have to feed, um, for quite a long time, for 24 to 48 hours.
And this really is a horrible disease. I had a student some years ago who had chronic Lyme disease.
And again, uh, the primary symptoms you could kind of dismiss, right?
Flu like symptoms. You can develop this classic bull’s eye rash which is shown on the right, Erythema migrans, but you don’t have to get that right.
So you might have a tick bite. You might not think much about it.
You may or may not get a rash. And then if you don’t have treatment, this rash will clear whether you had it or not.
And then the second stage of the disease, which occurs in about 80% of patients,
is this really disseminated horrible disease with cardiac, neurological, skin lesions, um, and all sorts of non-specific things.
And it can frequently get misdiagnosed as M.S. because the patient may have lethargy and things, which is exactly what this student had.
And even with treatment, even if this is treated, these sort of immune symptoms can continue.
So it really isn’t a very nice disease and really quite, um, sort of silent and insidious.
Um, and yeah, you can go on to get arthritis, um, uh, even post antibiotic.
So it’s a really horrible disease.
And it’s difficult to know if you’ve been treated with antibiotics how to then eliminate these symptoms.
Um, so the other thing to say is that this disease is very difficult to diagnose,
primarily because you have very low levels of the spirochaetes within your system.
So generally it’s done through an antibody test.
There is this one B. burgdorferi sensu lato, which tends to have higher numbers in the body.
So it’s quite a difficult disease to diagnose.
It tends to be done by antibodies.
And it’s quite rare to detect the bacteria.
LEPTOSPIRA SPECIES
And the third spirochaete that I want to talk to you about.
is the causative agent of leptospirosis, Leptospira interrogans.
and this is translated into the Greek verb, which means question mark.
because they have little hooked ends.
Um, and this causes the most common zoonotic infection in the world.
So you get about 60,000 deaths and there’s about 1 million cases.
So it is a big problem and it’s transmitted through urine either directly or through infected soil.
And the thing about this disease is, for most people, you’ll get a very sort of mild flu like disease,
but occasionally it can cause this really serious Weil’s disease, which is characterised by multi-organ failure and can rapidly lead to death.
leptospirosis- still in swimming pools
Um, recently, what they’ve discovered is that in some parts of the world, it’s actually other
animals that play a more important reservoir than rats such as cattle, goats and sheep.
And so this has been quite, important research because it suggests we need to start looking at that reservoir.
Um, and so this this could play a role in preventing leptospirosis.
But again, it’s fairly recent considering how prevalent this disease is.
This is only in 2018. Um, so it’s fairly, um, recent.
LEPTOSPIROSIS, WEIL’S DISEASE
And this is somebody with Weil’s disease.
as I said, you can get very mild flu like symptoms or you can get this horrible jaundice, with a 5 to 15% mortality rate.
And it’s characterised by vascular collapse, thrombocytopenia, haemorrhage, hepatic and renal dysfunction.
So it’s a really, really horrible disease.
Um, and again, I’m not sure they really understand why some people get a mild disease and some people get this really serious Weil’s disease.
but yeah, it’s really horrible. You have to be hospitalised and get hooked up to receive fluid replacement and frequently have to have dialysis because of the renal dysfunction.
Treatments
So how can we treat these diseases? Fortunately, there is treatment.
Um, the brilliant thing about syphilis is it has remained sensitive to penicillin, which is just fantastic.
Um, so generally, people will get injected with a single injection of IM penicillin, so that’s really good.
If you could get a patient and diagnose them, treat them, send them away.
Um, if they have secondary or tertiary syphilis, they have to have higher doses of penicillin and three doses this time.
And obviously with tertiary syphilis, it may become almost untreatable because the damage is as has already been done,
Lyme disease can be treated with doxycycline, amoxicillin or cefuroxime
And it has to be treated for a long time. Um, but as I said, despite treatment, patients frequently have long term symptoms
and Weil’s disease you don’t really need to treat anyone with the mild symptoms,
but obviously the severe symptoms you need antibiotics and you need to be in intensive care.
I mean, it’s a really serious disease. So, um, dramatic interventions there.
Key Questions
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