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:
Douglas Young A new horizon for preventive vaccines against tuberculosis Madrid7 th May 2014 Mycobacterium tuberculosis Evolution of Functional Diversity
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 Proc Biol Sci B. 278: Carter et al PLoS One 7:e % reduction in seropositive disease 79% reduction in IFN conversion Field trial of BCG in badgers Gloucestershire groupno of badgers incident cases % of total cases CIF probability control ( ) vaccinated ( )0.001 unvaccinated cubs from vaccinated setts had a reduced ESAT6/CFP10 IFN response vaccination interrupts onward transmission
Berg et al PLoS One 4:e5068Firdessa et al 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 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
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
Global phylogeny of M. tuberculosis Comas et al Nat Genet 45:1176
Rose et al Genome Biol Evol 5: 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
M. tuberculosis M. canettii M. canettii 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
M avium M. paratuberculosis M. yongonense M. kansasii M. gastri M. ulcerans M. marinum M. canettii M. tuberculosis M. canettii 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 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
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 M. smegmatis JS62348
MKAN_ plasmid MKAN_ chromosome 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 pMK % identical sequence in M. yongonense plasmid pMyong1 100% identical sequence in M. parascrofulaceum (plasmid?)
yrbE1Amce1A mce1Bmce1C mce1DlprK mce1FRv0175 Rv0176 Rv % yrbE1B fadD5 Rv0178 mce1R %78%66%63%61%64%71%52%50% 49% transposase M. chubuense plasmid pMYCCH01 M. tuberculosis Mce1 MCE locus on pMYCCH01
M. kansasii M. gastri M. ulcerans M. marinum M. canettii M. tuberculosis M. canettii M. xenopi no more horizontal gene transfer! niche isolation? cobF deletion
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 Future Microbiol 8:1405
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?
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?
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
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?
human lung industrial remediation mycobacteria freely exchanging flexible functionality immunological vomiting niche adaptation transmission cycle no turning back (no horizontal transfer) niche isolation