slide1 n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Douglas Young PowerPoint Presentation
Download Presentation
Douglas Young

Loading in 2 Seconds...

play fullscreen
1 / 18

Douglas Young - PowerPoint PPT Presentation


  • 114 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Douglas Young' - raleigh


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Mycobacterium tuberculosis

Evolution of Functional Diversity

Douglas Young

A new horizon for preventive vaccines against tuberculosis

Madrid 7th May 2014

slide2

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

slide3

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

slide4

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

slide5

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

slide6

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

slide7

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

slide8

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

slide9

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

. . .

slide10

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?)

slide11

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

slide12

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

slide13

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

slide14

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?

slide15

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?
slide16

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

slide17

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?

slide18

niche

adaptation

human lung

mycobacteria

freely exchanging

flexible functionality

immunological

vomiting

transmission

cycle

niche

isolation

no turning back

(no horizontal transfer)

industrial remediation