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Douglas Young

Mycobacterium tuberculosis Evolution of Functional Diversity. Douglas Young. A new horizon for preventive vaccines against tuberculosis Madrid 7 th May 2014. Field trial of BCG in badgers. Gloucestershire 2005- 2009. 844 badgers caught and sampled disease detection by serology

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Douglas Young

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  1. Mycobacterium tuberculosis Evolution of Functional Diversity Douglas Young A new horizon for preventive vaccines against tuberculosis Madrid 7th May 2014

  2. Field trial of BCG in badgers Gloucestershire 2005-2009 844 badgers caught and sampled disease detection by serology 262 captured more than once were test negative on initial capture 22 incident cases 74% reduction in seropositive disease 79% reduction in IFNgconversion unvaccinated cubs from vaccinated setts had a reduced ESAT6/CFP10 IFNg response vaccination interrupts onward transmission Chambers et al. 2011. ProcBiolSci B. 278:1913-20 Carter et al. 2012. PLoS One 7:e49833

  3. Bovine TB in Ethiopia A. bovine TB in rural cattle 30000 carcasses screened in abattoirs 1500 lesioned animals, 170 ZN+ cultures low prevalence 0.5 – 5% 58 M. bovis isolates 8 M. tuberculosis isolates (12%) B. bovine TB in urban intensive farms high prevalence > 50% post-mortem: 67 cultures from 31 animals 67 M. bovisisolates 0 M. tuberculosis isolates M. tuberculosis can cause disease in individual animals, but it doesn’t establish an efficient transmission cycle Berg et al. 2009. PLoS One 4:e5068 Firdessa et al. 2012. PLoS One 7:e52851

  4. THE CONCEPT I want to have a vaccine that interrupts transmission: can I target some layer of species-specific biology that is required for an effective transmission cycle? THE MODEL the ideal vaccine candidate biology involved in effective transmission biology involved in making a lesion THE STRATEGY I don’t have an experimental model for transmission, so I’m going to try and infer biology by looking at evolution of human isolates

  5. Global phylogeny of M. tuberculosis Lineage 7 Lineage 4 Lineage 1 Lineage 3 Lineage 5 Lineage 2 animal strains Lineage 6 Comas et al. 2013. Nat Genet 45:1176

  6. Do toxin-antitoxin modules regulate “persistence”? transcription higher in Lineage 1 transcription higher in Lineage 2 Rose et al. 2013. Genome BiolEvol 5:1849-62 in vitro transcription profiling reveals strain variation in transcript abundance but there’s very little evidence of genomic diversity of TA modules

  7. Number of TA modules M. tuberculosis M. canettii 60008 M. canettii 70010 Mycobacterium sp. JDM601 M. gastri M. kansasii M. xenopi M. yongonense M. paratuberculosis M. smegmatis mc2 155 M. avium M. marinum M. abscessus M. ulcerans M. phlei blue: chromosome red: plasmid M. hassiacum Mycobacterium sp. MCS M. gilvum M. smegmatis JS623 M. chubuense

  8. TAs and phylogeny high TA mycobacteria (>10 modules) in red Mavium 100 deletion of lon protease 88 M.paratuberculosis M.yongonense 65 rpoC sequence, GTR+G+I, Maximum Likelihood phylogeny, 100 bootstrap ddn nitroreductase lactate dehydrogenase M. kansasii 76 100 M. gastri M. ulcerans lactate dehydrogenase ddn nitroreductase 79 lon protease 100 M. marinum M. canettii70010 ddn nitroreductase 90 lactate dehydrogenase M. tuberculosis 100 99 M. canettii60008 100 M. xenopi Mycobacterium sp. JDM601 62 M. phlei 96 M. hassiacum M. smegmatisJS623 57 M. chubuense 100 plasmids 100 M. gilvum Mycobacterium sp. MCS 100 M. smegmatisMC2 155 M. abscessus 0.02

  9. What else is carried on mycobacterial plasmids? toxin-antitoxin modules metal ion detox and efflux cytochrome P450s adenylatecyclases diguanylatecyclases Type VII secretion loci mce loci . . .

  10. ESX locus on pMK12478 MKAN_ chromosome 00225 00220 00215 00210 00205 00200 00195 00160 00155 72% 34% 55% 50% 45% 95% 91% 53% 56% MKAN_ plasmid 29420 29425 29430 29435 29440 29445 29450 29455 29460 29465 29470 29475 PE PPE 72% 31% 57% 48% 45% 94% pseudo 52% 57% Mtb Rv1783 Rv1798 Rv1793 Rv1797 Rv1792 Rv1784 Rv1796 Rv1794 Rv1795 eccA5 eccE5 mycP5 eccD5 esxN esxM eccB5 eccC5 Rv1786 Rv1791 Rv1788 Rv1785 Rv1790 Rv1787 Rv1789 PE19 PPE27 PPE26 PE18 PPE25 cyp143 99% identical sequence in M. yongonenseplasmid pMyong1 100% identical sequence in M. parascrofulaceum(plasmid?)

  11. MCE locus on pMYCCH01 transposase transposase M. chubuenseplasmid pMYCCH01 5788 5775 5787 5786 5785 5784 5783 5782 5781 5780 5779 5778 5777 5776 80% 78% 60% 66% 63% 61% 64% 71% 52% 50% 50% 49% mce1R Rv0178 Rv0177 yrbE1B fadD5 Rv0176 Rv0175 mce1F lprK mce1D mce1C mce1B mce1A yrbE1A M. tuberculosis Mce1

  12. no more horizontal gene transfer! niche isolation? M. kansasii M. gastri M. ulcerans M. marinum M. canettii70010 M. tuberculosis M. canettii60008 M. xenopi cobF deletion

  13. Deletion of cobF(vitamin B12) in M. tuberculosis cobF M. canettii deletion in M. tuberculosis M. tuberculosis other methyltransferases may (partially?) compensate Gopinath et al. 2013. Future Microbiol 8:1405

  14. The Great M. tuberculosis Schism pyruvate kinase SNP alanine dehydrogenase frameshift PhoR SNP cobL (+MK) deletion (RD9) more relaxed approach to host restriction? increasing species adaptation?

  15. M. tuberculosis may have evolved to rely on vitamin B12 provided by the host? niche adaptation • bioavailability of B12 in primates versus ruminants? • effect of diet – vegetarian versus meat-eating? • gut microbiome?

  16. The optional metabolome of vitamin B12 AMINO ACID BIOSYTHESIS DNA REPLICATION methionine propionyl CoA deoxyribonucleotide methylcitrate (PrpCD) methylmalonate (MutAB) MetE MetH NrdEF NrdZ homocysteine succinate ribonucleotide B12-independent B12-dependent ENERGY

  17. Lineage 5 Lineage 6 22 independent SNPs and frameshifts predicted to impair function of MetH Lineage 4 Lineage 2 reduced reliance on B12-dependent pathways? Lineage 3 Lineage 7 Lineage 1 post-Neolithic?

  18. niche adaptation human lung mycobacteria freely exchanging flexible functionality immunological vomiting transmission cycle niche isolation no turning back (no horizontal transfer) industrial remediation

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