Sunday, 20 November 2016

Blame the Europeans

You know when you drive an unfamiliar car and you have to find your way round all these knobs and buttons to make the car go in the direction you want it to go in? M. tuberculosis has the same problem when it comes to the human immune system. This can make things tricky as it’s a pathogen that practices immune subversion rather than immune evasion—driving the immune response in its own favour rather than hiding.

A lot of the time, specific lineages of TB stick to the human genetic backgrounds that they’ve grown-up infecting. Even as global travel increases and the world gets smaller, these associations between TB lineage and their preferred flavour of human host persist. Over millennia, specific lineages of M. tuberculosis have evolved alongside specific human populations, learning all our secrets and finding ways to navigate our immune systems. Faced with an unfamiliar host, however, the pathogen can struggle.

But some lineages and sub-lineages are better at adapting to new host backgrounds than others. They’re the ‘generalists’ of the TB family. In comparison, the less-adaptable strains are known as ‘specialists’ and more or less stick to geographically restricted populations. They’re the ones who, if they ever go on holiday, demand a hire car exactly like the one they have at home. ‘I can’t be dealing with these fancy Japanese cars’, they say. ‘Give me a nice, British-made Rover.’

This idea of co-evolution and adaption is one I talk about in more detail in my book Catching Breath - The Making and Unmaking of Tuberculosis. The book is basically a scientific biography of TB exploring how M. tuberculosis came to be the world’s biggest infectious disease killer and how science is going to kill it right back. It comes out next summer as part of the Bloomsbury Sigma imprint of popular science books.

Here, though, I wanted to mention a new paper that came out last week from Sebastian Gagneux’s lab in Switzerland. In it, he looks at the success of M. tuberculosis lineage 4. It’s the most adaptable lineage, making its home on every inhabited continent—a generalist lineage that’s found its success thanks to both biological and social phenomena, according to Sebastian’s study. 

The team used SNP-typing and targeted whole genome sequencing to look at the genetic differences between 3,366 lineage 4 strains isolated from 100 different countries. They used the differences to break down lineage 4 into several sub-lineages. Some were generalists found in multiple locations; others, in comparison, were more isolated and rarely strayed outside of small regions of Africa, for example.

Like I said, M. tuberculosis doesn’t hide from the immune system. It wants to be recognised so the bits of the pathogen on the immune system’s watch list don’t tend to vary much at all. But Sebastian’s study showed that the generalists are more immunologically versatile than their specialist counterparts. This is likely because they have evolved to deal with a wider range of host genetic backgrounds and have had to come up with ways to ensure they get their own way no matter who they infect.

The paper was also interested in the sub-lineage known as L4.1/LAM. L4.1/LAM, like Starbucks, is on a mission to take over the entire world. It’s found everywhere from Africa to Australia. The scientists used the genetic differences between members of L4.1/LAM to predict its geographical origin. According to the results, it first emerged in Europe then, as us troublesome Europeans spread around the world, we took our TB with us.

It’s a common story when it comes to TB. The disease is among the world’s oldest and its history is twisted up with that of us humans. The spread of TB around the world tracks with human migrations; explosions in M. tuberculosis populations overlay with human upheavals. Understanding the co-evolution of M. tuberculosis and the human immune system has consequences for, in particular, vaccine design. How do we vaccinate against a pathogen that uses the immune response for its own benefit and how do we make sure any vaccine works in every population where not only the predominant lineage differs but so does the host’s genetic makeup?

Stucki D et al. 2016. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sub-lineages. Nature Genetics.

Yu Y et al. 2015. RASP (Reconstruct Ancestral State in Phylogenies): a tool for historical biogeography. Molecular Phylogenetics and Evolution. 87: 46-49

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