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Douglas Young A new horizon for preventive vaccines against tuberculosis Madrid7 th May 2014 Mycobacterium tuberculosis Evolution of Functional Diversity.

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Presentation on theme: "Douglas Young A new horizon for preventive vaccines against tuberculosis Madrid7 th May 2014 Mycobacterium tuberculosis Evolution of Functional Diversity."— Presentation transcript:

1 Douglas Young A new horizon for preventive vaccines against tuberculosis Madrid7 th May 2014 Mycobacterium tuberculosis Evolution of Functional Diversity

2 844 badgers caught and sampled disease detection by serology 262 captured more than once were test negative on initial capture 22 incident cases Chambers et al. 2011. Proc Biol Sci B. 278:1913-20Carter et al. 2012. PLoS One 7:e49833 74% reduction in seropositive disease 79% reduction in IFN  conversion Field trial of BCG in badgers Gloucestershire 2005-2009 groupno of badgers incident cases % of total cases CIF probability control821417.1(10.8-25.9) vaccinated17984.5(2.4-8.2)0.001 unvaccinated cubs from vaccinated setts had a reduced ESAT6/CFP10 IFN  response vaccination interrupts onward transmission

3 Berg et al. 2009. PLoS One 4:e5068Firdessa et al. 2012. PLoS One 7:e52851 high prevalence > 50% post-mortem: 67 cultures from 31 animals 67 M. bovis isolates 0 M. tuberculosis isolates Bovine TB in Ethiopia 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%) A. bovine TB in rural cattle B. bovine TB in urban intensive farms M. tuberculosis can cause disease in individual animals, but it doesn’t establish an efficient transmission cycle

4 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 CONCEPT 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 THE STRATEGY biology involved in making a lesion biology involved in effective transmission the ideal vaccine candidate THE MODEL

5 Global phylogeny of M. tuberculosis Comas et al. 2013. Nat Genet 45:1176

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

7 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 M. hassiacum Mycobacterium sp. MCS M. gilvum M. smegmatis JS623 M. chubuense Number of TA modules blue: chromosome red: plasmid

8 M avium M. paratuberculosis M. yongonense M. kansasii M. gastri M. ulcerans M. marinum M. canettii 70010 M. tuberculosis M. canettii 60008 M. xenopi Mycobacterium sp. JDM601 M. phlei M. hassiacum M. smegmatis JS623 M. chubuense M. gilvum Mycobacterium sp. MCS M. smegmatis MC2 155 M. abscessus 100 99 100 96 100 57 62 100 88 90 79 76 65 0.02 rpoC sequence, GTR+G+I, Maximum Likelihood phylogeny, 100 bootstrap high TA mycobacteria (>10 modules) in red TAs and phylogeny plasmids lactate dehydrogenase lon protease ddn nitroreductase ddn nitroreductase lactate dehydrogenase ddn nitroreductase lactate dehydrogenase deletion of lon protease

9 What else is carried on mycobacterial plasmids? toxin-antitoxin modules metal ion detox and efflux cytochrome P450s adenylate cyclases diguanylate cyclases Type VII secretion loci mce loci... organismadenylate cyclase domains M. tuberculosis16 M. marinum31 M. ulcerans15 M. smegmatis mc 2 1557 M. smegmatis JS62348

10 MKAN_ plasmid 29475 2947029465 2946029455 294502944529440 2943529430 29425 29420 MKAN_ chromosome 00155 00160 00195 0020000205 00210 0021500220 00225 Rv1783 Rv1784 Rv1792 Rv1793 Rv1794 Rv1795 Rv1796 Rv1797 Rv1798 Rv1785 Rv1786 Rv1787 Rv1789 Rv1790 Rv1791 Rv1788 eccB5 eccC5 esxMesxN eccD5mycP5 eccE5eccA5 cyp143 PPE25PE18PPE26 PPE27PE19 PE PPE 56%53% 91% 95%45% 50% 55%34% 72% 57%52% pseudo 94%45% 48% 57%31% 72% Mtb ESX locus on pMK12478 99% identical sequence in M. yongonense plasmid pMyong1 100% identical sequence in M. parascrofulaceum (plasmid?)

11 yrbE1Amce1A mce1Bmce1C mce1DlprK mce1FRv0175 Rv0176 Rv0177 80% yrbE1B fadD5 Rv0178 mce1R 578757855784578357825781578057795778577757865776 60%78%66%63%61%64%71%52%50% 49% 5788 5775 transposase M. chubuense plasmid pMYCCH01 M. tuberculosis Mce1 MCE locus on pMYCCH01

12 M. kansasii M. gastri M. ulcerans M. marinum M. canettii 70010 M. tuberculosis M. canettii 60008 M. xenopi no more horizontal gene transfer! niche isolation? cobF deletion

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

14 pyruvate kinase SNP alanine dehydrogenase frameshift PhoR SNP cobL (+MK) deletion (RD9) The Great M. tuberculosis Schism 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 homocysteine methioninepropionyl CoA succinateribonucleotide deoxyribonucleotide MetEMetH methylcitrate (PrpCD) methylmalonate (MutAB) NrdEFNrdZ AMINO ACID BIOSYTHESIS DNA REPLICATION ENERGY B12-independent B12-dependent The optional metabolome of vitamin B12

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

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


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