Taking a close look at TB

TB kills up to 2 million people per year but despite being relatively well studied, how the bacterium spreads in populations and how differences in the genetic makeup of the bugs affect that transmission isn't well understood. Judith Glynn from the London School of Hygiene and Tropical Medicine is now using a molecular genetic approach to look for answers.

Judith - What we've done in our study in Northern Malawi is study TB over a very long period and we try and identify everybody with tuberculosis in the population. And then by looking at the actual strain of TB they're infected with, in detail we can begin to work out who might have transmitted to whom and therefore, understand transmission in more detail.

Chris - This is by comparing the genetic sequences of the different isolates from the different patients and so I presume you're finding unique genetic sequences that go with certain  individual cases of TB and you can then track where they go through the population.

Judith - Yes. So, we're looking at the whole of the genetic code of the TB in these different people. Previous studies had used much cruder techniques and they told us quite a lot about where TB was being transmitted, but this new technique known as, whole genome sequencing, we get almost the whole genome. We compare it between people and look at the number of changes in the TB carried by different patients. And by comparing the number of differences we can say who might have transmitted to whom.

Chris - When you look at the trends that come out of the study between who gets infected and who gives what to whom. Are there any sort of generalizations and general points that emerge? And also are there any surprising points? Are there things that emerge from this study that actually we haven't seen before or didn't expect to see?

Judith - To start with, what we expected to see. We find more transmission from people who've got smear positive disease. That's to say they've got so many bacilli in their sputum that you can actually see them under a normal microscope. So, those people transmitted more than people who haven't got that level of disease. We know that, but it shows that the method is working, that we can actually see that in the data. Now to move on to what's sort of newer is the difference between the lineages of TB, these different strains of TB which divided into lineages. So, some previous studies had suggested differences between lineages. What's important in this study is that the population has all of the four different lineages but they're not linked to particular population groups. In studies in the West, you often find a particular lineage is much more common in particular immigrant groups and you might get different transmission dynamics within those groups and different probabilities of transmission. In this population, there was no association with immigration status into this area, which is actually a rural area in Northern Malawi. And so, the differences that we found by lineage are probably more likely to tell us about real differences between lineages in terms of transmissibility.

Chris - And what are the implications of what you found in this study?

Judith - I think it will help us understand more about why some people get ill and some don't. The different lineages really do seem to be behaving differently. For example, the Lineage-1 was the least transmissible and that's been suspected before, Lineage-1 strains seem to come from Southern India. And it's been thought that the TB there was a little bit less virulent. Similarly, Lineage-2, that one seemed to transmit more and again, fits with what people have suspected. Less known was that Lineage-3 also seemed to transmit more and that hasn't been shown previously.

Chris - What keeps these things circulating then if they're at this sort of disadvantage relative to other strains? Why haven't they slowly, by evolution, just been selected out and outcompeted by the more transmissible forms?

Judith - One possibility is the effect of HIV. And interestingly Lineage-1 which is the one which appears to transmit less was more common in people with HIV. So, that would fit with it being less likely to give rise to active disease in people who are not immuno-suppressed.

Chris - Do you think your findings are generalizable if we were to go out of this population in Malawi and drop into another African country, an Asian country, or even into the middle of London. Would we see the same phenomenon?

Judith - I think the differences between the lineages are probably biological in that there don't seem to be differences within the population that explain them here. Whether you would see the same in other populations where there may be differences in whom the different lineages are in if they're in different immigrant groups with different mixing patterns, you might see different effects. But to the extent they're biological differences, and then you should actually see them in different populations. And I think in terms of why it matters is it can give us clues as to what the virulence factors might be. So, the next step would be to actually look in much more detail at what other differences between the lineages at a genome level that might explain some of these differences in virulence and transmissibility. Does that give us clues to, for example, drug design or even an understanding why some people get sicker than others?