Madrid 7 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 ID: 913015
Download Presentation The PPT/PDF document "Douglas Young A new horizon for prevent..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Douglas Young
A
new horizon for preventive vaccines against tuberculosis Madrid 7th May 2014
Mycobacterium tuberculosis
Evolution of Functional Diversity
Slide2844 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. 278:1913-20
Carter et al. 2012. PLoS One 7:e49833
74% reduction in seropositive disease
79% reductionin IFNg conversion
Field trial of BCG in badgers
Gloucestershire 2005-
2009
groupno of badgersincident cases% of total casesCIF probabilitycontrol821417.1(10.8-25.9)vaccinated17984.5(2.4-8.2)0.001
unvaccinated cubs from vaccinated setts had a reduced ESAT6/CFP10 IFNg response
vaccination interrupts onward transmission
Slide3Berg et al. 2009. PLoS One 4:e5068
Firdessa
et al. 2012. PLoS One 7:e52851
high prevalence > 50%
p
ost-mortem: 67 cultures from 31 animals
67
M. bovis isolates 0 M. tuberculosis isolates
Bovine TB in Ethiopia
30000 carcasses screened in abattoirs1500 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
Slide4I want to have a vaccine that interrupts transmission:c
an 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
b
iology involved in
m
aking a lesion
b
iology involved ine
ffective transmissionthe ideal vaccine candidate
THE MODEL
Slide5Lineage 4
Lineage 3
Lineage 2
Lineage 6
a
nimal strains
Lineage 5
Lineage 1
Lineage 7
Global phylogeny of
M. tuberculosis
Comas et al. 2013. Nat Genet 45:1176
Slide6Rose et al. 2013. Genome
Biol
Evol 5:1849-62Do toxin-antitoxin modules regulate “persistence”?
transcription higher in Lineage 1
transcription higher in Lineage 2
i
n vitro
transcription profiling reveals strain variation in transcript abundance
but there’s very little evidence of genomic diversity of TA modules
Slide7M. tuberculosis
M.
canettii 60008M. canettii 70010
Mycobacterium sp. JDM601
M.
gastri
M.
kansasii
M.
xenopiM. yongonense
M. paratuberculosisM.
smegmatis mc2 155
M. avium
M. marinum
M. abscessusM. ulceransM. phleiM. hassiacumMycobacterium sp. MCSM. gilvumM. smegmatis JS623M. chubuense
Number of TA modules
blue: chromosomered: plasmid
Slide8M
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
100
100
100
100
96
100
57
62
100
88
90
79
76
65
0.02
rpoC
sequence, GTR+G+I, Maximum Likelihood phylogeny, 100 bootstrap
h
igh TA mycobacteria (>10 modules) in red
TAs and phylogeny
plasmids
l
actate
dehydrogenase
l
on
protease
d
dn
nitroreductase
d
dn
nitroreductase
l
actate
dehydrogenase
d
dn
nitroreductase
l
actate
dehydrogenase
deletion of
lon
protease
Slide9What else is carried on mycobacterial plasmids?
toxin-antitoxin modulesm
etal ion detox and effluxcytochrome P450sadenylate cyclasesdiguanylate cyclasesType VII secretion loci
m
ce
loci
. . .
organism
adenylate cyclase domains
M. tuberculosis16M.
marinum31M. ulcerans
15M.
smegmatis mc
2 1557
M. smegmatis JS623 48
Slide10MKAN_
plasmid
29475
29470
29465
29460
29455
29450
29445
29440
29435
29430
29425
29420
MKAN_
chromosome
00155
00160
00195
00200
00205
00210
00215
00220
00225
Rv1783
Rv1784
Rv1792
Rv1793
Rv1794
Rv1795
Rv1796
Rv1797
Rv1798
Rv1785
Rv1786
Rv1787
Rv1789
Rv1790
Rv1791
Rv1788
eccB5
eccC5
esxM
esxN
eccD5
mycP5
eccE5
eccA5
cyp143
PPE25
PE18
PPE26
PPE27
PE19
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?)
Slide11yrbE1A
mce1A
mce1B
mce1C
mce1D
lprK
mce1F
Rv0175
Rv0176
Rv0177
80%
yrbE1B
fadD5
Rv0178
mce1R
5787
5785
5784
5783
5782
5781
5780
5779
5778
5777
5786
5776
60%
78%
66%
63%
61%
64%
71%
52%
5
0%
5
0%
49%
5788
5775
transposase
transposase
M.
c
hubuense
plasmid pMYCCH01
M.
t
uberculosis
Mce1
MCE locus on pMYCCH01
Slide12M.
kansasii
M.
gastri
M.
ulcerans
M.
marinum
M.
canettii
70010
M. tuberculosis
M.
canettii
60008
M.
xenopi
n
o more horizontal
g
ene transfer!
n
iche isolation?
cobF
deletion
Slide13cobF
d
eletion in
M. tuberculosis
M.
canettii
M. tuberculosis
Deletion of
cobF
(vitamin B12) in
M. tuberculosis
o
ther
methyltransferases may(partially?) compensateGopinath et al. 2013. Future Microbiol 8:1405
Slide14pyruvate kinase SNPalanine dehydrogenase
frameshiftPhoR SNPcobL
(+MK) deletion (RD9)The Great M. tuberculosis Schism
more relaxed approach
t
o host restriction?
i
ncreasing
s
pecies adaptation?
Slide15M. tuberculosis may have evolved
to rely on vitamin B12 provided by the host?
niche adaptationbioavailability of B12 in primates versus ruminants?
e
ffect of diet – vegetarian versus meat-eating?
g
ut
microbiome?
Slide16homocysteine
methionine
p
ropionyl
CoA
succinate
ribonucleotide
deoxyribonucleotide
MetE
MetH
m
ethylcitrate(
PrpCD)
methylmalonate
(MutAB)NrdEFNrdZ
AMINO ACID
BIOSYTHESIS
DNA REPLICATION
ENERGY
B12-independent
B12-dependent
The optional
metabolome
of vitamin B12
Slide17Lineage 5
Lineage 6
Lineage 4
Lineage 2
Lineage 3
Lineage 7
Lineage 1
22 independent
SNPs and
frameshifts
p
redicted to impair
f
unction of
MetHreduced reliance onB12-dependentpathways?post-Neolithic?
Slide18h
uman lung
industrial remediation
m
ycobacteria
freely exchanging
f
lexible functionality
i
mmunological
vomiting
n
iche
adaptation
t
ransmission
c
ycle
n
o turning back
(no horizontal transfer)
n
iche
isolation