Lecture 14- neisseria Flashcards
What do you know already about Neisseria???
So as a starting point, what do you guys already know about Neisseria?
Do you know anything about Neisseria? Do you know, perhaps, um, the species that mainly cause disease in this group of organisms?
Does anybody know anything about Neisseria? So you would have all had a vaccine against one of the diseases, um, that one of the species, uh, causes.
Does anybody know what that is? Anybody.
Think about what sorts of particularly for you guys.
Um, a really important disease. Does anybody know?
One is a meningitis. Meningitis?
Yes. So one of the organisms that we’re going to talk about today is Neisseria meningitidis, which causes meningitis.
And all of you will have received, um, maybe 1 or 2 different types of vaccines against meningitis because meningitis is very prevalent in children,
but it also has a secondary peak in your age group.
And indeed, we a few years back, we did have an outbreak of meningococcal meningitis on campus.
So does anybody know another disease that is caused by Neisseria?
Anybody else? Yeah. Gonorrhoea.
Yeah. So completely different diseases.
And what’s remarkable about these two organisms is that they are incredibly similar but have completely different lifestyles,
uh, so they’re kind of fascinating from that point of view.
NEISSERIACEA are extraordinary
Um, okay. So as I said, Neisseria that rather an extraordinary genus of bacteria.
Um, they’re really, really peculiar. They can be, uh, thyere gram negative.
So, um, they have a gram negative cell wall.
Now, what does that tell us? Can anybody remember anything about gram negative and gram positive cell walls?
Does anybody know the fact that that gram negative.
What will they immediately tell us about them? Anybody
So both gram positive and gram negative bacteria contain peptidoglycan.
That’s good. It’s remembered something. It’s a very unique, uh, component of bacterial cell walls.
Anything else about gram negative cells?
Probably feels like an enormously long time ago that you were thinking about them.
So they have outer membranes, um, which means that they tend to be less susceptible to antibiotic killing.
So there’s less antibiotics that can kill gram negative organisms because a lot of our antibiotics target peptidoglycan,
and their peptidoglycan is covered by an outer membrane.
And this slightly protects them. So these organisms can, uh, can be aerobic.
They can be rods, they can be cocci. And also, rather bizarrely, they can be multicellular.
Now, I always say this over and over again and everyone mocks me for it, but.
Well, you have to remember in science is the bacteria do not read the rules, so they do not know that they have to follow these rules.
So there will be always exceptions to the rule, right?
Because they don’t know they have to follow them. So we learned that bacteria are single cells.
But here you can see these organisms here.
These bonkers organisms that are found in the mouth are multicellular.
Okay. So they didn’t know that they were meant to be single cells.
And then, um, you’ve got all these aren’t that interesting.
Like Snodgrassella rather interestingly named groups of Neisseria.
neisseria gonorrhoeae vs neisseria meningitides
Um, but we’re really going to be concentrating on these two really important pathogens, Neisseria gonorrhoea and Neisseria meningitidis.
And what’s brilliant about these bacteria is you don’t really have to think too hard about what disease they cause because,
you know theyre named after the disease.
Key questions
So the questions and I like to think of science in questions, um, is what are the microbiological characteristics of these two species?
What are the differences between them? Um, what are the important challenges in controlling these two, um, organisms and the diseases that they cause?
General characteristics
So the general characteristics, this is what they look like under electron micrograph.
They come in little pairs. Um, uh, and they look like kidney beans.
Um, so that gram negative diplococci and this is what they look like, you can see that little rough surfaces there.
And they have this really weird characteristic, um, they’re not motile, but they appear to be twitching.
And this is because they are highly covered in Pilli, um,
which are these surface appendages which are really important for attaching to other cells.
So they’re non motile, but they sort of twitch.
General Microbiology
Here are some of the sort of general microbiological characteristics, um, of these organisms.
And so they have a lot of shared characteristics.
So they’re gram negative diplococci. They’re oxidase positive.
They require CO2 for growth. Um, actually, um, gonorrhoea has a higher requirement for CO2 than meningococci.
You can kind of almost get away with growing Neisseria meningitidis without CO2.
They’re not motile, but they look like theyre twitching.
Um, uh,
meningococcal can be intra and extracellular whereas Neisseria gonorrhoea are always found intracellular usually in polymorpho-nuclear sites.
Um, the interesting thing about their meningococcal is many you will have them up your nose without any symptoms. So this is a this is an organism that doesn’t really want to be a pathogen.
It wants to just live up your nose quite happily with its friends.
Um, it’s a sort of accidental pathogen, whereas Neisseria gonorrhoea is always pathogenic.
So its identification indicates disease.
And another key difference between these organisms is the production of, um, capsule.
And this is, um, really important. Does anybody know?
So a capsule is basically a polysaccharide cloak that surrounds a bacterial cell wall.
Um, and these, capsules are really important for protecting bacteria against the immune system
because they basically cloak all the antigens that are present on the bacterial cell wall.
Does anybody know what organisms.
And that’s not just bacteria. It’s also fungi that have capsules.
All of them, um, have been associated with what type of disease does anybody know?
So anybody remember what it enables you to do?
Have a guess. Right. Neisseria meningitidis has a capsule
So what disease do you think it might allow you to cause?
Yeah. Yes. Perfect meningitis.
Because it seems that you need this capsule to cross the blood brain barrier.
Okay, so it’s a good rule of thumb when you’re
revising or answering a question if one of the questions says which of these organisms has a capsule.
Think about the diseases that they cause. So Cryptococcus, for example, has a capsule.
Streptococcus pneumoniae has a capsule. These are all organisms that can cause meningitis.
So another key difference is that Neisseria gonorrhoea has become incredibly resistant to antibiotics.
And this has gotten to such an alarming state that we’re now in a situation where people are getting almost untreatable gonorrhoea,
which is absolutely bonkers, right? Because gonorrhoea used to be treated with a short course of penicillin.
Now, fortunately, we don’t see resistance in Neisseria meningitidis.
And this is very fortunate because meningococcal meningitis can kill you within 24 hours.
So we wont be told if it was antibiotic resistant as well.
Um, so antibiotic resistance um, is quite rare.
So that’s really fortunate. But we’ll discuss a little bit why.
Um, there might be a few alarm bells going on off there.
Um, and that’s to do with the fact that they may share the same niche in certain situations.
And so there is a caution that there
if we ended up with antibiotic resistant meningococcal, we’d been in a really bad situation.
Biochemically. So we used to do this when I worked in the lab.
We would distinguish these two species by biochemical tests.
So gonorrhoea is only able to utilise glucose whereas meningo can use glucose and maltose.
And then another key difference between these organisms is that there are several available vaccines for meningococcal meningitis.
Um, but despite a lot of research, we don’t yet have a vaccine for gonorrhoea.
And obviously with the increase in antibiotic resistance, this is quite important, right?
Because if we aren’t able to control a disease with drugs, we need to have a way to prevent people from getting it in the first place.
Lifestyles Vs diseaseVery similar genetically BUT have very different lifestyles
So as I said, um, what’s incredible about these two species is they’re very,
very genetically similar, but they have extraordinarily different lifestyles.
So, uh, Neisseria meningitidis. It can live in the upper respiratory tract, and it really doesn’t want to be a pathogen.
And to be honest, we still don’t understand why it decides to leave that niche and, uh, cause a very invasive meningitis with or without septicaemia
And there’s a lot of research into when what happens, why is carriage versus disease and whether,
you know, because all this disease is sort of, uh, a dance between the host and the pathogen.
Is it that some individuals are very, very susceptible?
Um, so I remember once. So we used to have a group that worked on, meningo they don’t do any, any work anymore.
Um, and I remember there was somebody who had never been colonised with meningos,
and they were almost pleading him to try and work out what was special about him,
to try and understand, you know, why some people go on to get disease,
and you can have sporadic cases of meningococcal meningitis and you can have, um, epidemic outbreaks.
And particularly these are highly prevalent on the meningitis belt right across the middle of Africa.
So Neisseria gonorrhoea primarily infects the urogenital epithelia.
It can cause epididymitis, cervicitis endometriosis, pelvic inflammatory disease,
but it can also cause pharyngitis, and it could also cause conjunctivitis.
And this can be a very serious problem in babies because it can be transmitted from mother to child during birth.
Um, it can be chronic and it can also be asymptomatic.
And this is obviously a big problem. Right. Because then people don’t get treated and they pass it on to somebody else.
Um, very, very rarely you can get disseminated gynaecological disease.
And this is really associated with people who have, uh, the underlying conditions.
And this, this is rare but very serious.
So you can see two different, uh, lifestyles there.
But as I said, they’re very, very similar. And these are diseases that only affect humans, right?
These are human specific diseases. Now what?
Why do you think that is an issue or might have thwarted progress in understanding these diseases?
Can anybody think on. Yeah, it’s very difficult because of a lack of animal models
So there are animal models for these diseases but they’re not very good.
Um, and they’re quite controversial in the field.
So there is a mouse model, um, that’s used for meningitis, but it involves overloading the mouse to make them more human like.
Um, and lots of people don’t like it.
So obviously when you don’t have any way of doing animal experimentation, it can really impinge, um, on the development,
um, the scientific development, the understanding and the development of new therapeutics and, vaccines.
N. meningitidisA feared pathogen that really wants to be a commensal
So this is this is really where Neisseria meningitidis lives in the nasopharynx.
Um, and understanding this carriage is really where the field is in meningococcal disease, because now we have vaccines.
Right. And in a way um, part of the reason we don’t do research at surrey anymore is because when the vaccine,
the new vaccine came out for serogroup B meningitis, it sort of knocked the bottom out of the research.
So now what people are trying to do is understand carriage.
And as I said, carriage can range from 10 to 55% in healthy people.
Can anybody guess who has the highest carriage?
Does anybody know or wants to guess who has the highest carriage of meningitis?
Normally it’s kids right in this situation, but hey, it’s you guys, right?
University students have the highest carriage of Neisseria meningitidis.
And it’s thought that carriage offers some immunity.
So obviously, when they start introducing the vaccines, there was some concern that if the vaccines prevented carriage,
that actually you’d end up with a more susceptible population.
So it’s sort of counterintuitive, but actually the vaccines don’t seem to have affected carriage,
which is kind of good, but also kind of bad if you think that, that is the reservoir of infection.
so that’s kind of really interesting.
And that’s where the research is understanding this carriage.
What are the symptoms of meningitis?
But I still think it’s a useful, um, video to show how many of you were aware.
Um, oh, I would go that’s the other video, I think.
I that’s. That was going to happen.
Why was that? Here we go. Let’s get rid of her.
Um, how many of you were aware that meningitis was an issue?
Um, amongst university students?
Many of you. Some of you. Yeah. Okay.
Um, so what are the signs and symptoms, then, of meningitis that you picked up from them?
Cool. Yeah. Photophobia.
sensitive to light. What else?
Yep. Cold? Yeah. That had cold limbs.
He wanted to sit by the radiator, didn’t he? What else could.
Rash? Yeah, a rash that doesn’t belong when you put, uh.
Um, not everybody gets a rash, though. It’s really important to remember that.
What else? God. High fever.
Yeah, very high fever. It was obviously delirious.
And what else? What was his first symptom that he described?
Headache? Yeah. Really severe headache. Um.
So. Excellent.
Meningococcal disease affects mainly children
so one thing I supposed to be aware of is the other group of patients that that get this disease is young babies.
Right? So here you can see that most people who get meningococcal meningitis are babies.
Right. And then you get this second peak, um, here.
Um, so less than four or less. Um, one.
What do you think the problems with babies when you’re thinking about the symptoms?
Yeah, exactly. They can’t tell you.
Oh, I’ve got a really bad headache. And what happens with babies is they tend to go floppy.
And then it’s really, really important that parents get them to the hospital immediately because this is such a serious disease.
The rash. So not many patients don’t get the rash.
The rash is very diagnostic. But if you think babies are always getting viral rashes, you know it would be easy to miss diagnose it.
Um, so Neisseria meningitidis causes 1.2 million cases per annum.
And in the global north, we get these winter peaks of infection.
Does anybody know why it might happen in the winter?
Can anybody think why?
So the answer is we don’t really know.
They also think that because there’s central heating it might dry out inside the nose.
And this might somehow increase the chances of it going from being living in your nose to travelling up .
We don’t really properly know
the disease is very prevelent in Africa, “When you live through one of these meningitis epidemics, it sears your soul.”
So as I said, um, the other place which is has these horrible epidemics of, um, meningococcal meningitis is in this what’s called the meningitis belt.
So here you can say it stretches from, um, Senegal, uh, and the Gambia in the west to Ethiopia in the east.
So this is about 430 million people that live in that area.
And you get epidemics every 8 to 10 years.
it is associated with very hot, dry conditions.
And again, they don’t really understand why. But one of the theories is that perhaps it changes that nasopharyngeal by causing it to dry out and that affects somehow its commensal properties.
But we really just don’t understand it
Neisseria gonorrhoea: GONOCOCCUS
So, uh, Neisseria gonorrhoea
to start to think about how different this, um, organism is.
Um, this was first described, this disease was first described by Hippocrates and it was called strangury the pleasures of Venus.
the person who discovered it used Robert Cox gram staining technique, to stain gonococci from infected individuals.
And he was the first person that was able to visualise them.
And, uh, here you can see this is a beautiful electron micrograph.
And here you can see the beautiful pili that make them twitch.
And they’re credibly long. And these lovely diplococci.
So, uh, Neisseria gonorrhoea, if you remember Koch and his postulate, um, of course,
gonorrhoea didn’t satisfy Kochs postulate because we didn’t have an animal model.
If you remember the postulate, you know, the organism has to be isolated in pure culture.
If you reinfect an animal, they get the disease.
That’s the classical way in which Koch showed that a disease was caused by infectious agents rather than spontaneously, which was thought of at the time.
symptoms of gonorrhoea
So I’m sorry about this so early in the morning, but this is just to show you, um, the classic, symptoms of gonorrhoea, getting this,
a discharge, burning when urinating and the dogma has been in the field that men usually get symptoms, but women can be frequently asymptomatic.
That’s kind of been debunked now. Now, and is fairly well recognised that men can be asymptomatic and have chronic infections too.
Conjunctivitis
if, as I said, it can also cause a conjunctivitis and this is particularly a problem in babies.
So if the mother has gonorrhoea, the baby can, uh, acquire this conjunctivitis during birth.
And, um, this is a really horrible infection, and you urgently need to get this baby I.V. and antibiotics.
Otherwise, it can really, um, perforate the cornea and permanently cause damage to the eye.
Rebound of Gonorrhoea
Um, so it’s really quite horrible. So what was happening at the moment, um, which is also happening with syphilis,
is we seemed to have this rebound effect, um, a sort of post-Covid effect.
Um, we now have, um, massive increases in gonorrhoea.
And this is a really big problem. Um, from the one hand, because it’s very antibiotic resistant and more difficult to treat,
it also increases your risk of acquiring HIV because it damages, the mucosal surface.
It increases the risk of ectopic pregnancy, um, increases infertility in both sexes.
And, um, there really is poor understanding in the transmission, um, uh,
networks, um, and the reservoirs, um, and this rebound gonorrhoea, by the way,
they think, I mean, they don’t know, but they think part of the problem is that during Covid,
no one was getting diagnosed with sexually transmitted diseases.
Okay. So lots of people may have had infections that they didn’t get treated.
In addition to that, um, people may have had more risky behaviour post-Covid.
And also people might be more likely to have unprotected sex.
So we’ve now seen this huge increase.
And here you can kind of see split up into ages.
The particular age group, um, that is particularly, uh, more at risk, um, in this sort of 15 to 24 area, you see the highest, um, rates of gonorrhoea.
Laboratory Diagnosis
So how do we diagnose these diseases.
So with meningococcal meningitis, how do you think it’s primarily diagnosed.
Symptoms.
Yeah. You can’t afford to muck around. It’s better to just give someone antibiotics.
So when I was a young biomedical scientist on call, I got a CSF from a baby and I managed to find one pair of gram negative diplococci.
And basically this doctor said to me, oh well, wait and see if you culture it in the morning.
And I said to him, no,I don’t think so. I think you need to talk to your consultant.
And indeed, if they waited till the morning, that baby would have been dead.
So you haven’t got time. Um, so often the diagnostic test
are done post-treatment and the samples classically are CSF and blood samples.
Obviously culture takes too long, but it’s important, particularly if you want to look at the epidemiology and see whether you have an outbreak.
And uh PCR is also used in diagnosis
gonococcal disease
So um, when I worked as a biomedical scientist, if someone turns up at a sexually transmitted clinic,
we would take lots of swaps from them and do direct microscopy.
Right. Because the thing about sexually transmitted disease clinics is people often don’t come back.
So you kind of want to get them in and treat them while they’re there.
And this is what you would classically say, um, from an exodate in a positive patient.
So you’ve got these lovely gram negative diplococci, um, mostly extracellular, but they can be intracellular.
Um, now we have nuclear amplificiation tests.
And that’s the diagnostic method used. and old fashioned counterculture methods are still also used.
But obviously they take a day or two to get the results.
What’s the advantage of culturing the organism?
Why do you think it might be good to culture? What would it allow you to do?
Yeah. See which antibiotics might be useful, to treat the patient with.
The drugs don’t work
So, as I said, gonorrhoea here is a time course for, um, antibiotic resistance in this organism.
It’s been absolutely terrifying. Um, and here you can say in 2018, we got our first, um, XDR, extremely drug resistant case of TB.
I always remember my biology teacher telling me that when she was at university,
she’d always remember when she’d say, you know, all these guys drinking lemonade at the bar because they were having penicillin for their gonorrhoea.
Well, now you don’t get penicillin for gonorrhoea because it just doesn’t work.
And indeed, we’re in a situation now where people have to take co treatment.
Um, part of the reason and that was a terrible blunder with gonorrhoea.
So we had um in the UK, in Malaysia they had this massive drive to treat chlamydia.
So committing as the number one cause of sexually transmitted diseases.
And what they did was they had a drive. They gave people erythromycin to treat chlamydia.
Unfortunately they gave them the dose of erythromycin that wouldn’t kill gonorrhoea.
So they indeed contributed to the rise in resistance to erythromycin
so resistance has has spread incredibly quickly.
So people are now really having to think about novel ways to treat gonorrhoea because to me,
it’s kind of incredible that we have untreatable, um, gonorrhoea.
gonorrhea may soon be resistant to all antibiotics
So as I said, it’s possible that gonorrhoea may become untreatable.
Um, and yeah, this screening program where they used this low dose erythromycin was a massive mistake.
Um, and definitely contributed to the rise in erythromycin resistance.
I did read this really cool paper. So Neisseria are very weird, they can take DNA. they can just take it up.
And, um, I saw this really cool paper where basically they had designed DNA that when Neisseria took it up, it killed them.
And I thought that was kind of a cool treatment. Method.
Um, because obviously, um, we’re having to look for things aside from antibiotics to treat these diseases,
particularly as the big Pharma are not really interested in developing anti-infectives anymore because that doesn’t make them, um, enough money.
Treatments
Um, so in contrast, fortunately, meningococcal disease is very treatable.
Um, benzyl penicillin or amoxicillin, giving IV, and drug resistance is incredibly rare.
Um, obviously you have to be treated for this, uh, toxic shock, um, with fluids.
Um, the patients will often be given adrenaline, um, and, uh, frequently steroids, um, and often before the antibiotics,
because one of the problems with meningococci is what causes all the symptoms is the lipopolysaccharide that’s coming off the cell wall.
So you can imagine when you give a patient antibiotics, if this bacteria starts to lyse, you have the potential to make their symptoms worse.
So they’re often given steroids to dumb down the immune system.
And then there’s lots of experimental therapies such as anti cytokine and anti-endotoxin.
And it’s very important that contacts are also treated um with antibiotics to ensure that they don’t also get um disease.
So as I said a ceftriaxone and azithromycin dual therapy is now used for gonorrhoea.
Um, but there really, really is a big push, um, to explore alternative strategies for treating this disease.
Meningococcal Vaccines
Um, we have lots of vaccines now available, um, against meningococci.
Um, it has different serogroups. So it’s very difficult to produce, um, a completely cross protective vaccine.
Um, and although we have multi-component vaccines, they, they don’t protect you against everything.
Um, so there is a quadrivalent one A,C,Y, W-135.
This is very useful in the African meningitis belt conjugate-C vaccine you would have all had as babies.
And that has really dramatically, um, reduced the cases of type C.
Bexsero B Vaccine (4CmenB)
And then the last one was this Bexsero B vaccine
Um, so the problem with Group B meningococci is that all the other vaccines are based on the cell wall,
but it is thought that the cell wall of group B, it’s made of sialic acid.
We have lots of sialic acid. So it’s not very immunogenic.
So they had to use a different strategy to make this vaccine. it’s a really interesting vaccine because it was developed by reverse vaccinology, So it was developed using the genome, and it was the first vaccine that was developed like this.
Now, what’s fabulous about this vaccine, is that once they introduced it, it did two things.
It seems to be cross protective against other serotypes.
And what they’ve noticed is that people who’ve had that vaccine there is less gonorrhoea.
So there is some indication that this vaccine might protect you against gonorrhoea.
And there’s a big push now. The protection isn’t great.
It’s about 40%. But there’s quite a big push to introduce this vaccine for people at particularly high risk, which are men that have sex with men.
Um, and so basically there’s a push to introduce that, um, as a vaccine.
And, and it looks exciting. So now. Now there is some glimmer that we may be able to get a gonorrhoea vaccine, because I think we really do need one.
so 40% protection against gonorrhoea.
eliminating meningitis across africas meningitis belt
So obviously these vaccines, uh, they get made and they’re all for, uh, the global North, right?
They’re all for the rich people. And that’s a problem because a lot of the meningitis happens in the meningitis belt.
And you’ll see this with drugs, with vaccines, with everything, you know.
Um, the disparity between the vaccine development,
which is often done in the global South and then they’re unable to, to actually afford this treatment.
But the W.H.O., um, along with actually has developed an affordable vaccine,
Gaining control of gonorrhoea
So in terms of, um, controlling gonorrhoea, really what we are dependent on is appropriate antibiotic treatment,
fast diagnosis, identification of AMR and, uh, partner notification.
So really control of this disease.
And really what the thrust is to develop novel approaches to treat this disease.
there’s some hope that we might be able to develop a vaccine because if the meningococcal vaccine has some effectiveness,
effects of PsA-TT vaccine
Shared signatures: What’s similar and what’s different?
one thing I didn’t tell you.
So one thing that terrifies me is now they’ve started sequencing everything because high throughput sequencing is really cheap.
What they’ve found is that some cases of gonorrhoea or some neisseria that has been identified,
in the genital tract has been uh identified as Neisseria meningitidis.
Now this to me is absolutely terrifying. So that has to be immediately notified because that suggests
whilst the recommendation is if the patient hasn’t got symptoms, not to worry about it.
However, that says to me that we could have a situation where Neisseria meningitidis becomes antibiotic resistant.
Now hopefully that’s just something for a horror film. But if that happens, we will be in a really bad situation because people would die pretty quickly.
We would have never noticed that before that would have never been possible.
But because now we can sequence organisms, we can differentiate them.
