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.