Session 10: The Immune Response in Health and Disease

Transcript of Part 2: An Introduction to Tuberculosis: The Pathogenic Personality of the Tubercle Bacillus

00:00:07.18	My name is Lalita Ramakrishnan and I'm a professor of Immunology and Infectious diseases at the
00:00:12.17	University of Cambridge.
00:00:14.11	I work on tuberculosis, and I'm going to introduce you to this disease and share with you some
00:00:21.00	vignettes about the curious pathogenic personality of its causative agent, Mycobacterium tuberculosis,
00:00:28.18	which we often also call the tubercle bacillus.
00:00:32.17	Now, tuberculosis is mostly a disease of the lungs, and what do you think of when you...
00:00:40.10	when you think of a TB patient?
00:00:41.18	Do you think of someone who's thin, very thin, emaciated, and in fact the disease has been
00:00:48.01	called consumption over the ages.
00:00:51.02	People also tend to have fevers, loss of appetite, they cough a lot, and often, as you can see
00:00:58.06	here, they cough up blood.
00:01:01.09	If you were to look at an X-ray of their chest,
00:01:04.07	you would see that their lung is ravaged by TB.
00:01:08.06	As well, you can see a big cavity in there that is teeming with bacteria that they're
00:01:13.13	coughing up in that sputum, there.
00:01:16.09	Now, while we often think of TB as a lung disease, in fact TB can affect multiple organs.
00:01:23.16	So, on that upper left panel, there, you see a lung that has been ravaged by TB.
00:01:30.08	But you can see here that many, many other organs -- pretty much every organ in the body --
00:01:35.07	can be affected by TB.
00:01:37.03	The only thing is that TB, as I have taught my medical students for decades, now -- is
00:01:45.12	transmitted through the lungs, as you can see here.
00:01:50.00	The bacteria spew out of an infected patient and land in the lungs of an unfortunate individual
00:01:55.22	who happens to be next to this person.
00:01:57.15	So, TB in any other organ is going to be a dead-end disease, and so in that... in terms
00:02:04.23	of the pathogen's survival it doesn't do very much for the pathogen.
00:02:10.20	Now, TB was discovered by these two physicians: Jean-Antoine Villemin was a French physician
00:02:21.10	who first identified TB to be an infectious disease, and then Robert Koch really elaborated
00:02:31.00	on this elegantly in 1882.
00:02:33.21	So, before this for many, many centuries, people had recognized... well, not centuries,
00:02:40.18	even -- millennia... people had recognized that TB was a single disease entity.
00:02:45.19	The ancient Greeks knew this, for example, but it's these two gentlemen who... who identified
00:02:51.22	it as an infectious agent, and then Koch actually figured out that the disease was caused by
00:02:57.09	this particular bacterium.
00:02:59.08	Now, at the time, in the late 1800s, when these umm... when... when Villemin and Koch
00:03:05.17	were... were making these important discoveries, TB was a terrible problem in Europe.
00:03:12.03	So, a seventh of Europe's population was dying of this disease, and a quarter of... of the
00:03:22.17	working adults of Europe were... were dying of TB.
00:03:26.06	Now, imagine how that would be to have a quarter of the workforce decimated
00:03:30.18	by a single infectious disease.
00:03:33.15	And, in fact, we all know that there are many, many famous people who died of TB,
00:03:38.22	and I've shown...
00:03:40.07	I'm showing you some of their pictures, here,
00:03:43.06	and you can see that these are all young European men.
00:03:46.12	Well, one of them, the guy on the right there, Ramanujan, is obviously not a young European
00:03:50.20	man -- he was an Indian man -- but it turns out that he... he was a mathematical genius
00:03:55.20	who was recognized by a mathematician in Cambridge, a guy called GH Hardy, and Hardy invited Ramanujan
00:04:03.23	to come to Cambridge and... and do some math with him, and that's when Ramanujan came down
00:04:10.03	with TB and, as you can see, died some years later of it.
00:04:14.06	Now, we think of TB as a disease of the past, something that opera singers got, and poets
00:04:21.17	and musicians of the past, and maybe something that our grandparents had or if you're older,
00:04:27.19	like me, your parents, so here... so we here in North America and Europe really don't think
00:04:34.01	of TB as something that's... that is... is something to worry about anymore.
00:04:41.07	And, in fact, people will always... often ask me, is TB... oh, you work on TB?
00:04:46.22	Is TB back now?
00:04:48.14	But actually, TB never went away.
00:04:51.03	And, in fact, there's more TB now than there... there ever was before.
00:04:55.18	And, as you can see, it's concentrated in certain parts of the world: in Africa, as
00:05:02.02	you can see; and pretty much all of Asia; in Europe; and we have Russia that's affected
00:05:07.16	by TB; and... and then so is South America.
00:05:11.18	And... and this is very sad and so it's... it's important to stop for a minute and think
00:05:17.10	about why this might be the case.
00:05:19.06	And, in my view, there are two reasons for this.
00:05:22.18	The first is socioeconomic.
00:05:24.22	So, TB...
00:05:26.14	TB is a disease that disproportionately affects the poor, and this is because of the fact
00:05:35.16	that it transmits best in very... in crowded conditions with poor ventilation.
00:05:40.20	So, for example, your... your urban shantytown would be a place where TB would spread a lot.
00:05:48.00	In terms of who gets TB, malnutrition is a major risk factor, cigarette smoking is a
00:05:53.19	risk factor, environmental smoke... so, you know, smoke from... from... from cooking in
00:05:59.06	these crowded, unventilated environments is a risk factor.
00:06:04.08	And then there are more modern risk factors such as diabetes and also HIV.
00:06:10.18	And so about 35% of the... of the TB in the world today is amongst people who have HIV.
00:06:19.16	From a medical standpoint, there are all... there are issues that have made
00:06:24.06	TB difficult to eradicate.
00:06:26.17	So, for one thing, we don't have an effective vaccine against TB.
00:06:31.18	There was... there's a vaccine that was developed in 1921 -- I'll tell you a little more about
00:06:37.02	it later -- but it's basically not that effective.
00:06:40.06	In terms of antibiotics, we've had antibiotics since 19... and since 1950, and in fact the
00:06:48.11	anti... the four antibiotics that we use today were all developed between 1952 and 1962.
00:06:54.23	But the problem is that, to... to... to reliably cure TB, you need to treat a person with three
00:07:03.04	to four antibiotics for six months.
00:07:06.01	Now, anyone with... anyone of you who's tried to take antibiotics even for a week will...
00:07:11.17	will realize how hard that is.
00:07:13.22	When you start to feel better, you stop taking antibiotics.
00:07:17.07	Now, imagine if you had to do this in a place where you didn't have great access to health
00:07:23.07	care and perhaps you had to trek a long way to get your antibiotics, and it meant losing
00:07:28.09	a day's work.
00:07:29.09	So, it's not... it's easy to see why people stop taking medicines when they start to feel
00:07:34.04	better, and then... unfortunately what happens then is that the... the bacteria... the dis...
00:07:40.11	the infection... the disease relapses and they get contagious disease again.
00:07:46.19	And perhaps it's because of this that we now not only have TB persisting in the world,
00:07:53.14	but we also have drug-resistant TB.
00:07:56.09	And you can see that that has affected many parts of the world.
00:08:01.01	And drug-resistant TB comes in many flavors, depending on its extent.
00:08:07.00	So, if the bacterium is... is resistant to just the umm... the frontline drugs that I
00:08:14.10	told you about -- rifampicin and isoniazid -- then it's called multi-drug-resistant TB,
00:08:20.04	and then you have to treat the TB with other drugs that are not as good, for sometimes
00:08:24.03	as long as 18 months.
00:08:26.01	But then you can get what is called extensively drug-resistant TB or even
00:08:30.01	totally drug-resistant TB, which is basically a death sentence.
00:08:35.09	And so... so not only has the problem not gone away, but the problem has been compounded
00:08:43.20	by an alarming rise of resistant TB, and what... what is even more scary is that this multi...
00:08:51.12	extensively drug-resistant TB is perfectly able to transmit from individual to individual.
00:08:56.07	So, it's... it's a very good infectious agent.
00:08:59.20	So, let's have a quick look at the life cycle, the so-called life cycle of TB.
00:09:06.19	So, as I've alluded to, it's transmitted from person to person.
00:09:11.12	So, person coughs it up, it lands in the lung of the unfortunate individual next to them,
00:09:17.18	and then it gets into these cells that are called macrophages, and then tricks the macrophage
00:09:25.09	into taking it in, and forms these big aggregates that we call tubercles.
00:09:33.09	And then it has to break out of the tubercle to get out again and be contagious.
00:09:38.11	So, here is a fundamental difference between TB and some of the other... world's other
00:09:45.00	great bacterial killers: TB is completely dependent on causing... producing active disease
00:09:53.10	in the host in order to transmit.
00:09:56.02	So, it's sort of an obligate pathogen, which... and I use that word in a slightly different
00:10:02.08	sense than other people do at times.
00:10:05.10	Whereas if you think about other great bacterial killers, such as, let's say... let's take
00:10:12.03	the instance of plague... plague is really not a human... it's an accidental human disease.
00:10:17.17	So, this... this... this infection that has decimated humanity over the years is really
00:10:23.23	an accident, and human infection has no relevance to the evolutionary survival of... of the...
00:10:31.11	of the plague bacillus.
00:10:32.22	This is even true for things like the pneumonia bacterium, the pneumococcus, or the... or
00:10:37.18	the meningococcus that causes devastating meningitis, or your life...
00:10:43.07	your strep-eating streptococcus.
00:10:45.20	In all of these cases, these pathogens, these bacteria are just mucosal colonizers.
00:10:50.24	They live in our mucosal tracts and disease is occasional and accidental,
00:10:55.19	devastating as it is.
00:10:57.21	Not so for TB.
00:10:59.08	It needs to produce disease in order to... to transmit and survive, evolutionarily.
00:11:05.15	And, perhaps this explains why there's... there's a certain... there's a curious feature
00:11:12.10	that... that TB has, and that is it lacks what we call these classical virulence factors.
00:11:18.02	It lacks capsules that... that bacteria have to avoid being eaten by a macrophage, flagella
00:11:26.12	that bacteria use for motility, pili, toxins... pilis... pili are used for adhes... adhesion,
00:11:36.04	toxins are used... well, they're basically cell pois... they poison the host cell.
00:11:40.22	And in fact this is all talked about very nicely, both by Stanley Falkow and also by
00:11:46.14	Ralph Isberg in... in prior iBiology talks.
00:11:50.09	So, TB doesn't have any of these.
00:11:53.12	So, how is it so successful?
00:11:56.00	Well, there's... there's... there's a few things and I'm gonna illust...
00:12:01.02	I'm going to tell you about a couple of them.
00:12:03.08	So, one thing it does have is this waxy coat that, as you can see, gives the colonies a
00:12:09.12	characteristic appearance.
00:12:11.06	And then, if you were to stain the bacterium, and that... that stain there is actually taken
00:12:15.12	from a patient sputum, you'll see a... a... that it stains in the characteristic way,
00:12:22.18	where there are very specific stain and we call it... we call them acid-fast bacilli,
00:12:28.00	or some people call them red snappers, and this is because of that complex cell wall.
00:12:33.01	So, let's have a quick look at that cell wall.
00:12:35.22	So, if you look at this cartoon, that... there's a layer just above the cytoplasmic membrane
00:12:42.14	that is the peptidoglycan that... that pretty much all bacteria share.
00:12:47.13	But then you can see that, above it, it's got a really complex lipid... array of lipids.
00:12:54.08	Some of these lipids are complexed to sugars, others are complexed to proteins, and these...
00:13:01.11	this... these lipids seem to contribute a lot to the ability of mycobacteria to evade
00:13:08.09	the host and sort of... and... and... and... and... and be pathogens.
00:13:13.14	And I'm going to illustrate this for you with a discovery that was made in my lab by a PhD
00:13:18.16	student, CJ Cambier.
00:13:20.15	So, CJ wanted to really look at that very early event of TB.
00:13:26.20	So, after it gets into a host, how does it get into a macrophage and survive?
00:13:33.18	And macrophages are primary immune defense cells, and their job is to come to bacteria
00:13:41.05	and eat them and kill them.
00:13:43.20	And here's a video of a macrophage in culture eating bacteria.
00:13:48.15	You'll... you... this is a... umm...
00:13:52.00	I've...
00:13:53.00	I've...
00:13:54.00	I've basically taken this video from Manuel Amieva at Stanford, who also gave it to Stanley
00:14:00.02	Falkow, so you'll see this video in Stanley Falkow's iBiology lecture as well.
00:14:05.10	And you can see there's macrophages reaching out and eating bacteria, and Stanley refers
00:14:11.24	to this as macrophages eating peanuts from a bowl.
00:14:17.09	And now... when bacteria get in to macrophages, your garden-variety bacterium is killed, and
00:14:29.09	Stanley also talked about this in his lecture.
00:14:33.07	The way this happens is that the bacteria have on their surface those... you see those
00:14:38.07	funny little protrusions?
00:14:39.21	Those are called PAMPs, for pathogen-activated molecular patterns.
00:14:44.11	And these PAMPs activate in the host a pathway, a signaling pathway called
00:14:52.17	the Toll-like receptor signaling pathway.
00:14:55.08	And this pathway brings macrophages to the bacteria, and they'll eat them up and then
00:15:01.17	they can kill them using various microbicidal mechanisms.
00:15:04.22	So, you can see how, if a mucosal pathogen is... is in... in the right place for the
00:15:10.15	host, as in on the... on the outside of the mucosa, the host might let it be, but if it
00:15:15.01	tried to get in or get... or... or sort of started to wander, the host would send out
00:15:20.07	these macrophages that would then kill it.
00:15:23.14	Now, I've already told you that TB has to get in, it has to traverse this barrier to
00:15:29.06	get in -- it doesn't want to hang out with these pesky commensals.
00:15:32.11	It wants to get away from them and deal solely with the host.
00:15:37.05	And so, the TB has a... also has a ton of these PAMPs, so, how does it do this?
00:15:44.19	And what CJ found was that... that... that it uses some of these cell surface lipids
00:15:50.20	to coat the PAMPs.
00:15:51.20	So, the blue lipids here are something called PDIM, and PDIM coats these PAMPs, so now it
00:15:59.18	prevents TLR-mediated cell migration and engulfment.
00:16:05.00	But, then, it still needs to get in, so how does it do that?
00:16:09.16	Well, it adds on another lipid, and this lipid is a phenolic glycolipid, and this phenolic
00:16:15.08	glycolipid brings in a new and different kind of macrophage that is not microbicidal -- it...
00:16:24.18	it can engulf the bacteria, but it's permissive to the growth of the... of the bacteria.
00:16:30.09	So, in other words, mycobacteria are telling the host, "Thank you.
00:16:35.01	Don't worry about getting... about coming along with your macrophages.
00:16:38.23	I'll bring in a different kind of macrophage from you that can help me get in and survive".
00:16:44.05	So... so, here... just to reiterate, your bacteria on the left are your garden-variety
00:16:51.11	bacteria that will get killed by microbicidal macrophages that are recruited by the Toll-like
00:16:58.08	receptor pathway.
00:17:01.04	The mycobacteria don't use that pathway, they... they...
00:17:05.15	they hide from it from using these lipids.
00:17:08.22	And then, instead, they turn on... they... they activate the production of the chemokine
00:17:15.14	that recruits these permissive macrophages, that, as you can see, take up the bacteria
00:17:20.17	and then take them inside.
00:17:24.16	Now, this is a very... this... this... this use of the... of these two lipids is a very
00:17:29.08	nice evasion strategy, but if you think about it there's a... there's a problem with this.
00:17:34.15	And the problem is that we inhale TB and... into our nasal... into our nasopharynx, and
00:17:43.17	our nasal... our nasopharynx is full of bacteria that trigger TLR signaling.
00:17:51.15	So, even if TB has as a... the... even if mycobacterium has a way to evade Toll-like
00:17:58.11	signaling, it's... there's going to be a lot of Toll-like signaling going on right there,
00:18:05.21	and so it would be basically caught in the crossfire, in this battle between the host
00:18:11.16	and the bacterium, and... and... and essentially be collateral damage.
00:18:17.10	So, the bug has evolved a trick for this.
00:18:21.05	And that is that, unlike a lot of respiratory pathogens that are transmitted in the upper...
00:18:27.21	through the upper muc... respiratory mucosa, TB goes deep down inside.
00:18:34.05	And that's again illustrated in this cartoon you've seen before.
00:18:37.22	But watch of those red droplets, right?
00:18:40.00	They go deep down into the alveoli of the lung.
00:18:43.01	So, TB is not a disease of the upper respiratory tract.
00:18:46.09	It has to go really... down... deep down in small droplets that cont... that contain maybe
00:18:52.02	one, at the most, ten bacteria.
00:18:55.12	And this... this has been known for quite some time, both through human epidemiological
00:19:00.08	studies of how TB spreads and also through animal models.
00:19:04.22	And this is a very nice experiment that illustrates this.
00:19:07.21	So, these researchers at Johns Hopkins University in 1948 gave rabbits TB and they collaborated
00:19:16.08	with some engineers, and what they did was to devise a way to give rabbits TB so that...
00:19:23.21	in large droplets that contained 10,000 bacteria.
00:19:27.08	And these... these bacteria got stuck in the upper airway -- they could... they would follow
00:19:32.12	them just by killing rabbits and transecting them and seeing where the bacteria landed.
00:19:38.00	They also, then, took bacteria and put them in small droplets, so that one to three bacteria
00:19:42.18	were given to the rabbits, and they showed that they... these droplets went to the bottom
00:19:47.13	of the lung, to those alveoli that I talked about.
00:19:50.15	And then they followed what happens... happened to the rabbits, and you can see that the...
00:19:55.02	the rabbits that got more bacteria didn't get infected, whereas the rabbits that got
00:20:00.15	fewer bacteria got infected.
00:20:03.10	And so TB has known that more is not better -- less is better --
00:20:09.18	and has devised an additional strategy.
00:20:13.02	So, it has to use two lipids and it has to minimize its droplet size... size.
00:20:19.06	And so I illustrate for you, here, how TB escapes from the lower air... from the other
00:20:25.00	commensals and the... from the commensals, sorry, in the upper airway, and goes down
00:20:29.08	to the lower airway where it's all by itself and can do this
00:20:32.19	recruiting trick using its lipids.
00:20:36.01	Now, this has... there's... there's a couple of instructive points here.
00:20:44.05	One is that TB is less infectious because of... because it has to use the small-drop...
00:20:50.04	droplet strategy, it's actually not... not nearly as infectious as a common cold, or
00:20:55.05	measles, or other things that have to transmit in the upper airway.
00:21:00.14	Conversely, we could think about it as the commensal flora being protective against TB,
00:21:08.11	as we're finding more and more that they are against many infections, and TB doesn't seem
00:21:12.20	to be an exception.
00:21:15.11	But finally, TB has managed with this strategy and has been around since before the Neolithic
00:21:25.00	demographic trans... transition.
00:21:27.11	It's been around for something like 70,000 years.
00:21:31.06	So, the strategy is working very well for it.
00:21:36.02	So, these two lipids that I just finished telling you about turn out to be very important
00:21:41.24	determinants in the evolution of pathogenesis.
00:21:47.02	So, pathogenic mycobacteria evolved from soil-dwelling mycobacteria, and the acquisition of these
00:21:53.06	lipids was a major part of that step.
00:21:57.06	But, when we move on to now look at the next phase with... of... of the... of the life
00:22:04.21	cycle of these bacteria, which is living within this macrophage they've recruited and going
00:22:10.23	on to form the granuloma, there's a little bit of a surprise.
00:22:17.10	Because it turns out that the determinants that are used to survive in the macrophage,
00:22:23.07	bona fide virulence determinants that are studied quite a lot, turn out to be also present
00:22:30.18	in the soil-dwelling bacteria and it looks like they've just been repurposed from soil-dwelling
00:22:36.01	bacteria to... to confer virulence.
00:22:41.11	And one such example is the bacterial efflux pump, which... we don't know exactly what
00:22:48.05	it does in the soil, but it's very possible that this... this pump was used, or is used,
00:22:55.00	in the soil-dwelling mycobacteria to pump out antimicrobials or antibiotic-like molecules
00:23:02.19	that other soil-dwelling organisms put out, because it's... it's... it's a warfare out
00:23:08.01	there between these different organisms in the soil, and that's why a lot of antibiotics
00:23:12.12	were discovered in soil-dwelling organisms, to protect themselves against other organisms.
00:23:19.06	And this insight came from a graduate student in the lab, Kristin Adams.
00:23:26.00	And what Kristin found was that these bacterial efflux pumps got induced in the pathogenic
00:23:33.23	mycobacteria when they went into macrophages -- transcriptionally induced -- and they then
00:23:39.10	protected the bacteria against the macrophage and allowed them to survive in the macrophage.
00:23:45.23	So, they were macrophage-induced virulence factors.
00:23:50.08	So, here... but here's the twist: When Kristin looked a little bit more at this, she found
00:23:56.17	that they also mediate a phenomenon called bacterial tolerance.
00:24:01.20	So, bacterial... sorry, antibiotic tolerance.
00:24:06.11	Antibiotic tolerance is a phenomenon where the bacterium doesn't become genetically resistant
00:24:11.09	to an antibiotic, but nevertheless is... is... is phenotypically resistant to the antibiotic
00:24:19.17	in the... in the absence of any genetic resistance.
00:24:23.23	And it's often induced by particular environmental conditions.
00:24:27.19	This phenomenon of tolerance has been known for a long time and has been thought to be
00:24:31.11	the reason that TB takes so long to treat.
00:24:35.13	But the model that has been proposed for this is that when bacteria enter the host and enter...
00:24:42.13	and become part of the host granuloma, the tubercle, they essentially become dormant.
00:24:48.01	They undergo metabolic and a replicative arrest and, as a result, they become resistant to...
00:24:58.16	as resistant as intolerant to the antibiotics that typically tend to cart... target bacterial
00:25:06.10	determinants that are needed by actively growing bacteria, for example, your cell wall or your
00:25:11.02	ribosome or your transcriptional machinery.
00:25:15.13	And so, in this model, the slow...
00:25:18.02	most slowly growing bacteria would be the ones that would be the most tolerant.
00:25:22.18	And a lot of attempts to make new antibiotics to shorten TB treatment
00:25:27.24	are predicated on this model.
00:25:30.02	However, when... when Kristin looked, she found that these same pumps that allow the
00:25:37.01	bacteria to survive in the macrophage also mediate tolerance against frontline antibiotics
00:25:45.13	used for TB, and in fact every antibiotic that she tested was... was... the bacteria
00:25:54.11	underwent tolerance to that antibiotic upon entering a macrophage.
00:25:59.16	So, this has a profound clinical implication, because, now, the most... in her model or
00:26:05.19	in her observations, the most rapidly growing bacteria are the ones that are most tolerant
00:26:11.13	to the antibiotic, presumably because they're pumping it out.
00:26:15.18	And there's a... there's a... there's a... there's a clinical in here with this... with
00:26:22.16	this finding, because there are efflux pump inhibitors available,
00:26:27.21	bacterial efflux pump inhibitors.
00:26:30.00	Many of these just happen to be drugs that are around for other purposes.
00:26:34.02	And the one that we honed in on, or Kristin honed in on, was a drug called verapamil,
00:26:38.18	which is a calcium channel blocker that's used to treat high blood pressure, and cardiac
00:26:43.15	arrhythmias, and migraines.
00:26:46.09	And she found that if she treated the... the macrophages that were infected with verapamil,
00:26:52.09	along with the standard chemotherapy, they now did... they were killed much better with
00:26:57.13	standard chemotherapy.
00:26:59.00	And, based on these results, a clinical trial is... is going to start in India to see if
00:27:05.07	verapamil will shorten the course of treatment.
00:27:08.03	From an evolutionary standpoint, it's kind of interesting, because we're talking about
00:27:13.23	a... a pump that was used... or... and is used in soil-dwelling mycobacteria, presumably
00:27:20.02	to pump out antibiotics.
00:27:21.15	Then, over the course of most of the history of a... a pathogenic mycobacteria, it was
00:27:27.19	repurposed to... to fight macrophage defenses.
00:27:33.00	And then, in the last hundred years or so, since the advent of... or less, actually,
00:27:38.09	fifty years or so... since the advent of chemotherapy, that ancestral function has come back to help
00:27:45.02	the bacterium withstand the... the modern post-antibiotic era.
00:27:52.11	Moving along, we've got the bacteria now living in a... in what is called a granuloma, or
00:27:59.15	a tubercle, and the... while the initial cells that come and form this granuloma are macrophages,
00:28:07.10	the body then brings in, the host... the immune system brings in many more different cells
00:28:11.22	to... to come in and help fight the bacteria, and yet, in many... in... in a proportion
00:28:18.16	of cases, the bacterium is still able to survive in this rather complex structure.
00:28:25.05	And this brings me to... to a point that I want to make, which is that you'll hear many
00:28:32.24	times people say, and you'll read in books,
00:28:36.07	that a third of the world is infected with TB.
00:28:39.21	And the idea there is that they're infected with TB, they've got it under control, and
00:28:44.06	then it's ... but at any given time they can reactivate this latent disease, and... and
00:28:50.23	get transmissible... and get morbid and transmissible TB.
00:28:56.16	But, actually, this is based on... on the... on the TB skin test, which simply tests to
00:29:08.03	see if you've ever been infected with TB.
00:29:11.21	And so the fact that your skin tests positive doesn't mean you have TB infection now; it
00:29:16.15	means you once had TB infection.
00:29:18.13	You could still have it or you could have cleared it.
00:29:21.17	And if you really go and look at old epidemiological studies, old and new, you'll find that most
00:29:28.00	people who get infected with TB actually clear it using this arsenal of immune defenses,
00:29:36.06	and... and a combination thereof that I've listed for you, here.
00:29:41.20	And so, actually, most people eradicate TB, and a few people go on to have primary disease,
00:29:48.24	and latency and reactivation disease are no doubt present, but in my view, based on my
00:29:55.14	reading of the epidemiological studies, are a minority of... of cases.
00:30:02.16	And this is very nicely shown here, in a study done in Amsterdam, where contacts of active
00:30:10.02	TB sufferers were followed meticulously, and if they got TB at all they got it within the
00:30:16.01	first few months of exposure.
00:30:17.21	So, the immune system does a pretty good job of killing TB.
00:30:23.12	And if that's the case, then why don't we have a vaccine for TB?
00:30:27.18	Now, the vaccine for TB has been the Holy Grail.
00:30:30.13	Well, in fact... a vaccine for TB was made and was first administered in 1921.
00:30:36.05	It was a live attenuated vaccine.
00:30:39.19	And it's the... while it's the... we still use it to this day in highly endemic areas,
00:30:45.07	because it does offer a modicum of protection against disseminated TB and meningeal TB in
00:30:50.14	kids, which as you'll see in my third lecture is a terrible disease, but obviously we still
00:30:55.16	have a lot of TB, though it's the world's most widely administered vaccine, and that
00:31:00.21	means it doesn't protect very well at all.
00:31:03.20	And efforts to improve its efficacy, or to make whole new vaccines,
00:31:08.10	have not worked very well.
00:31:10.07	So, why is that?
00:31:11.18	Well, that's a paradox; we don't really understand why, but I'd like to tell you a few things.
00:31:16.06	First of all, most people don't get TB when they're infected -- they're protected naturally.
00:31:21.19	But, if you do get TB, then very... then you're not completely protected against a second
00:31:29.21	infection, which is different from the case of, say, smallpox, where if you get smallpox
00:31:34.18	once then you don't get it again.
00:31:36.15	People can get TB again.
00:31:39.00	On the other hand, there's very clear data that show that if you've... if your skin tests
00:31:45.03	positive but don't... never manifest a disease, you're... you're somewhat protected.
00:31:51.00	And that's nicely shown here in a study of nurses in Norway, who, in the pre-antibiotic
00:31:56.09	era, were found to be either skin test-positive and skin test-negative, and then they were
00:32:01.14	put amongst the TB patients to take care of them, and the ones who were skin test-negative
00:32:07.02	were more... much more likely to get TB.
00:32:09.11	So, these... the people who were skin test-positive but had never manifested TB were somewhat
00:32:14.13	protected against TB.
00:32:15.21	And if we can understand this, look at these data again with new eyes and understand them
00:32:20.20	a bit better, maybe we can try to think about ways to... to... to recapitulate the protection
00:32:29.03	that many people in fact seem to have.
00:32:31.19	So, in closing, we've got a bacterium here that is possibly one of the world's most successful
00:32:39.02	bacteria, that evolved from non-pathogenic environmental mycobacteria, doesn't really
00:32:44.23	have a great many classical virulence factors, but seems to use a sort of stealth mechanism
00:32:52.14	to survive.
00:32:54.19	And, even though it doesn't produce disease in most of the people that it infects, it's...
00:33:02.03	that's good enough for it, because it produces just enough disease to... to have survived
00:33:08.13	over the... over... over the eons.
00:33:12.08	That is not to minimize the impact of TB.
00:33:15.03	TB killed nearly eight... two million people last year, or year... in 2015, and caused
00:33:21.16	disease that... that debilitated them in about 10 million people.
00:33:27.22	And perhaps the most chilling thing to consider is that TB has been with us for more than
00:33:33.13	70,000 years and it's still with us.
00:33:36.23	It predates the transition to an agrarian culture.
00:33:40.21	It... it... it resisted urbanization -- in fact, it thrived with urbanization.
00:33:48.03	It's resisted modern medical technologies, like antibiotics and attempts to make a vaccine.
00:33:57.14	And so it's a... it's a... it's a pretty... it's a pretty tough and wily bacterium.
00:34:06.17	And if you stay tuned for parts two and three, I'll tell you about some more insights we've
00:34:11.16	had about this bacterium using a very interesting and unusual model to derive these insights.
00:34:23.12	Okay, thank you.