00:11:59.19 And then we could show all this by... by engineering fish that were transgenic, so that they had 00:19:27.08 And these... these bacteria got stuck in the upper airway -- they could... they would follow 00:29:40.15 But, in these... with these downstream drugs, they help one genotype but they have no effect 00:08:32.16 got quite lucky. 00:08:21.17 in the prior talk. 00:21:00.06 So, it's got a two-pronged effect. 00:28:15.23 bacteria, but it wasn't killing the macrophage. 00:18:55.12 And this... this has been known for quite some time, both through human epidemiological 00:20:12.12 But you're going to say, wait a minute, why would this spread the infection? 00:00:58.06 here, they cough up blood.

00:34:11.16 had about this bacterium using a very interesting and unusual model to derive these insights. 00:07:11.17 will realize how hard that is. 00:10:12.15 Let's have a look at the mechanics of the screen. Different immune cells arrive at the granuloma to surround the bacterial infection and fight the disease. 00:04:43.03 But the problem is, of course, they're expensive, there are ethical considerations, and obviously The riskof reactivation is markedly increased in pati… 00:11:13.20 But what was really exciting to us was that you could see, within a few days, 00:12:33.01 So, let's have a quick look at that cell wall. 00:29:27.24 I told you ahead of time... 00:28:39.21 And the idea there is that they're infected with TB, they've got it under control, and 00:18:50.13 the mutant macrophages, the few that do come, are just sort of sitting there 00:31:03.20 And efforts to improve its efficacy, or to make whole new vaccines, 00:23:06.13 that the variant had the same impact on severity of leprosy, 00:28:03.19 of reactive oxygen production, then he could convert the hyper-sensitive fish into a hyper-resistant 00:21:58.06 And so, a stand... what is now a standard of care treatment is helping one group 00:31:16.06 First of all, most people don't get TB when they're infected -- they're protected naturally. 00:05:50.10 and now they're in the extracellular environment, where they seem to be able to grow in a more 00:14:21.21 And he found that, instead, what was happening was that in the absence of leukotriene B4,

00:20:55.05 measles, or other things that have to transmit in the upper airway. 00:12:03.08 So, one thing it does have is this waxy coat that, as you can see, gives the colonies a 00:30:07.11 Okay. 00:00:08.02 My name is Lalita Ramakrishnan. 00:25:45.13 used for TB, and in fact every antibiotic that she tested was... was... the bacteria 00:00:49.13 in modern times, it can... it... things can go awry, and the immune system can cause inflammatory 00:22:17.10 Because it turns out that the determinants that are used to survive in the macrophage, 00:08:33.03 So, we mutated the bacteria and we saw how the mutants behave differently. After infection, M. tuberculosis pathogenesis occurs in two stages. 00:29:28.00 people who get infected with TB actually clear it using this arsenal of immune defenses, 00:10:55.19 devastating as it is. 00:33:15.03 TB killed nearly eight... two million people last year, or year... in 2015, and caused 00:13:09.00 mutant, and it was a... it was a... it was a very nice feeling to use a bacterial trait 00:18:40.18 And, even once they get into the granuloma, they behave very differently. 00:27:45.15 So, there were two pathways that were working to induce macrophage necrosis. Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action. 00:16:40.24 And the answer to this came of... both from Hannah's work and from a new graduate student Whereas the primary implant can occur anywhere in the lungs, for the progression from infection to disease, the tubercle bacilli must gain access to the 'vulnerable' regions in the apex of the lungs.

00:16:49.20 who joined, an MD/PhD student, Muse Davis, and what we found was happening was that, 00:27:53.24 But what Fran could show was that, if he knocked down those two pathways genetically, downstream 00:20:19.06 And so I illustrate for you, here, how TB escapes from the lower air... from the other 00:04:27.19 like me, your parents, so here... so we here in North America and Europe really don't think 00:27:13.23 a... a pump that was used... or... and is used in soil-dwelling mycobacteria, presumably 00:19:37.07 have tried for a very long time to see if some kind of 00:09:09.13 about what might be important for infection. 00:12:20.16 it has a lot more bacteria than its sibling that's on the top panel. 00:18:54.23 like bumps on a log. 00:05:22.18 The first is socioeconomic. 00:27:59.15 a tubercle, and the... while the initial cells that come and form this granuloma are macrophages, 00:13:52.04 And, when I was a bit slow to do this, he actually had someone in his lab make the mutation... Muramyl dipeptide (from peptidoglycan) complexed with mycolic acids can cause granuloma formation, phospholipids induce caseous necrosis. 00:26:10.05 the actual... in the macrophage itself, because it has to survive in there. 00:18:10.03 most, with the CTs being in the middle. 00:26:14.17 And the reactive oxygen, this excess of reactive oxygen, is that first good, because it can 00:14:13.07 have leukotriene B4. 00:09:25.09 into taking it in, and forms these big aggregates that we call tubercles. 00:00:33.02 which is the causative agent of tuberculosis, the bacterium that causes it, the bacteria 00:10:38.18 screen the fish. 00:22:46.13 But the question now is, how do... how do... how does this ESX1 locus induce the recruitment 00:01:13.13 coughing up in that sputum, there. 00:02:35.16 So... but it turns out that granulomas are very primitive structures; they've probably 00:23:19.06 And this insight came from a graduate student in the lab, Kristin Adams. 00:17:20.22 And then when he went and looked at a cohort of TB patients in Vietnam with the help of 00:12:28.00 infected macrophages. 00:06:51.14 to unravel the secrets of TB. 00:21:47.02 So, pathogenic mycobacteria evolved from soil-dwelling mycobacteria, and the acquisition of these 00:13:41.05 and eat them and kill them. 00:12:54.08 Some of these lipids are complexed to sugars, others are complexed to proteins, and these... 00:10:17.17 So, this... this... this infection that has decimated humanity over the years is really

The onset of active disease(primary disease) 4. 00:27:21.05 of contents, and that necroses the macrophage. 00:08:48.20 So, I've got for you, here, down below in... in the bottom panel, the... a human TB granuloma 00:09:13.23 And so we were thinking about doing this and... and then it all happened because of two things. 00:04:04.01 Like mammals, adaptive immunity takes a few weeks to develop in the fish. 00:02:37.11 the center has undergone necrosis and there's just a ton of bacteria in there, as we would 00:33:57.14 And so it's a... it's a... it's a pretty... it's a pretty tough and wily bacterium. 00:12:01.02 I'm going to tell you about a couple of them.

00:19:47.05 and this makes... makes people... this... this exacerbates the problem. 00:21:31.06 So, the strategy is working very well for it. 00:27:50.13 And the second of them is still being worked out. 00:01:32.10 individuals, reach the lung of an individual next to them, they get into macrophages, these 00:24:56.17 MMP9 in the macrophage, and now that... that is secreted and calls in new macrophages. 00:09:33.09 And then it has to break out of the tubercle to get out again and be contagious. 00:26:33.23 phase of the granuloma to promote its... its growth and expansion. 00:07:41.05 faculty member, and he gave me another key piece of advice. 00:24:17.15 So, it was behaving just like the bacterial mutant and therefore it was the partner. 00:16:08.24 formed by serial imaging, and what she showed was that, when the granuloma formed, the number 00:21:15.22 So, to summarize this, let's take a look at what happens in the mutant first. 00:25:06.10 determinants that are needed by actively growing bacteria, for example, your cell wall or your 00:05:42.22 This is a full-on necrosis, where the... the bacteria are spilled out of the macrophage 00:24:54.15 come out and they're growing happily extracellular. 00:00:30.24 Now, typically one thinks of infectious diseases as diseases of failed inflammation, and one 00:26:27.11 And so, mycobacteria are resistant to normal levels of reactive oxygen species, but when Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speaker and do not necessarily represent the views of iBiology, the National Science Foundation, the National Institutes of Health, or other iBiology funders. 00:19:52.04 that movie Jaws, where the... you know, the shark comes from below. 00:04:50.19 So, in... on this backdrop, my story and my engagement with TB and the granuloma came 00:24:06.11 Antibiotic tolerance is a phenomenon where the bacterium doesn't become genetically resistant 00:09:38.11 So, here is a fundamental difference between TB and some of the other... world's other

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