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Douglas Young A  new horizon for preventive vaccines against tuberculosis Douglas Young A  new horizon for preventive vaccines against tuberculosis

Douglas Young A new horizon for preventive vaccines against tuberculosis - PowerPoint Presentation

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Douglas Young A new horizon for preventive vaccines against tuberculosis - PPT Presentation

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

tuberculosis lineage canettii 100 lineage tuberculosis 100 canettii smegmatis b12 transmission plasmid isolates mycobacterium deletion dehydrogenase modules nitroreductase animals

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Slide1

Douglas Young

A

new horizon for preventive vaccines against tuberculosis Madrid 7th May 2014

Mycobacterium tuberculosis

Evolution of Functional Diversity

Slide2

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. 278:1913-20

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

Slide3

Berg 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

Slide4

I 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

Slide5

Lineage 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

Slide6

Rose 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

Slide7

M. 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

Slide8

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

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

Slide9

What 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

Slide10

MKAN_

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?)

Slide11

yrbE1A

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

Slide12

M.

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

Slide13

cobF

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

Slide14

pyruvate 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?

Slide15

M. 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?

Slide16

homocysteine

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

Slide17

Lineage 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?

Slide18

h

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