MICROBE 2018 recap - Evolution of Tuberculosis

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So it's Sunday...the meeting started Thursday night. Usually about this time, depending on how ambitious your schedule for the meeting, you are starting to get a little peek'ed and the sessions are starting to run together. For me - a good deal of money is spent coming to these conferences so I have a tendency to pack my schedule. This often times ends in overlapping sessions necessitating a cost/benefit analysis of whether I should risk missing the beginning of the next talk by running to the session after this one or stay in this session and listen to a talk that is perhaps less "soul-on-fire" interesting for me. In either case, you start tapping your coffee IV to make sure it's running only to realize that by this point you've probability built up a super human caffeine tolerance. Yet you still grab that cup and hold it at the morning sessions with such care and possessiveness you would think it a pot of gold.

So major kudos to Caitlin Pepperell and her ability to recapture my attention as my first coffee wore off and I started in on coffee #2. It helps that my next favorite bug - after Vibrio, is Mycobacteria

Evidence I stayed awake...the whole time:

You can decipher my notes above or just read the recap below.

Evolution of Mycobacterium tuberculosis

• So in talking about M. tuberculosis (Mtb) remember we are talking about an obligate human pathogen so any evolution that takes place in the organism is tied to humans and in fact we find that  bacterial population dynamics (or adaptation as viewed by the scale of mutations in Mtb) followed along the same timescale as human cultural adaptation.
• So in this relationship between pathogen and host you see the influence of culture on bacteria and bacteria on culture and we talked about this in terms of Neutral and Adaptive Interactions and their imprints on human culture.

Neutral Interactions - Mtb and Humans

• Reconstructing the global spread of Mtb
• 552 isolates
• Found that Mtb maps to historical shifts in human connectivity
• Trade and migration particularly along the silk road were important for transmission.

When we think of pathogen dispersal, we usually think of air flight and the massive rapid transit of pathogens and potential for outbreaks. However, don't underestimate the ability of historical trade routes to efficiently disseminate pathogens across large distances either; as evidenced by the high rates of exchange in Mtb

• Surprisingly though, China has not been seen as a big player in historical dispersal of Mtb, though China has been a big player in modern times. We determined this through looking at the migration of TB in China.
• 4 introduction events
• 4578 Mtb isolates
• Low diversity
• Hypothesis?
• Both the Ming and Qing dynasties had policies of seclusion which may have influenced the evolution of Mtb in the country and low diversity.
• Imprint of TB on Human Culture - the Sanitorium
• Prevalent 1830-1940s
• First time ever there was a single location/building/hospital dedicated to a single disease.

http://www.abandonedar.com/tuberculosis-sanatorium/

Adaptive Interactions - Drugs

"TB is singular in its dedication to kill us."

• So there is not real horizontial/lateral gene transfer for Mtb, it's clonal, highly clonal. This is interesting because when we think of AMR we think 'some sort of transfer' of genes.
• So how do you get resistance when you are following strict clonality?
• Mutation and Selection
• So mutations can confer resistance
• You can have a complement of antibiotic resistance genes which (along with others) can become targets of selection.
• These targets of selection can be subject to 'sloppy' or 'tight' mutability.
• In sloppy targets (ie. pncA) you can have lots of mutations with no trade off in fitness whereas in tight targets (ie. katG) anything beyond a single or very specific type of mutation and you suddenly get a drop in fitness.
• For more information on how this works check out "Signatures of selection at drug resistance loci in Mycobacterium tuberculosis" - bioRxiv article.
• Imprint on human cultural adapation
• You would think that admittance to Sanitoriums would decrease with the advent of drugs to combat the disease. In fact, this did not happen. With more drugs, more admissions were seen and sanitorium stays were longer.
• The standards in terms of 'clinical care' must have changed and in therapy you had several different types now: pre, mono, dual and triple therapies and there are trade off associated with different care.
• We don't start to see a drop off in Sanitorium care until around 1933-1959 coinciding somewhat with the start of chemotherapy for TB.

For other great articles out of the Pepperell lab check out:

• O'Neill, Mary B., et al. "Global Phylogeography of Mycobacterium Tuberculosis Reveals Role of Recent Human History in Pathogen Dispersal." AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY. Vol. 165. 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY, 2018.
• Not published yet so the link leads to the abstract, but promises to be quite interesting when published!
• O’Neill MB, Mortimer TD, Pepperell CS (2015) Diversity of Mycobacterium tuberculosis across Evolutionary Scales. PLoS Pathog 11(11): e1005257. https://doi.org/10.1371/journal.ppat.1005257
• Eldholm, Vegard, et al. "Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis." Proceedings of the National Academy of Sciences 113.48 (2016): 13881-13886.
• O'Neill, Mary B., et al. "Lineage specific histories of Mycobacterium tuberculosis dispersal in Africa and Eurasia." bioRxiv (2017): 210161.