Evolution of MDR-TB - APHL TB Conference... · Evolution of MDR-TB ... 106–110 In clinico Fitness...
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Transcript of Evolution of MDR-TB - APHL TB Conference... · Evolution of MDR-TB ... 106–110 In clinico Fitness...
![Page 1: Evolution of MDR-TB - APHL TB Conference... · Evolution of MDR-TB ... 106–110 In clinico Fitness of rpoA/C Mutations ... Ruedi Aebersold Uwe Sauer Tanja Stadler Jörg Stelling](https://reader034.fdocuments.in/reader034/viewer/2022052609/5b36e8207f8b9a310e8b8d7c/html5/thumbnails/1.jpg)
Evolution of MDR-TB
Sébastien Gagneux, PhD10th National TB Conference
Washington DC, 19th April 2017
Dept. of Medical Parasitology & Infection BiologyTuberculosis Research Unit
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Global TB Estimates (2016)
Number of cases
Number of deaths
1.8 million10.4 million
190,000480,000
All forms of TB
MDR-TB
XDR-TB ~ 48,000 ~ 24,000
>50% Case-fatality:→ Entering Post-Antibiotic Era !“Only” ~ 5% MDR / XDR
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“Drug‐Resistant Bacteria Are Less Fit”
DOGMA:
DS
DR
Fitness
Time
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Proportion MDR among new TB (2015)
WHO REPORT 2016
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0.01
0.1
1
10
100
29 76 54 67 4 32 78 4 29 79 34 33 77 30 31
Source reference
Rel
ativ
e fit
ness
of r
esis
tant
stra
ins
(log)
The Relative Fitness of DR Mtb is Heterogeneous
Borrell & Gagneux 2009 IJTLD 13: 1456-66
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Exploring the Role of Epistasis
Epistasis
Drug-resistancemutation(s)
Compensatorymutations
Strain geneticbackground
“Success”of MDR Mtb
Borrell & Gagneux 2011 Clin Microbiol Infect 17: 815–820
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DR
DS
Fitn
ess DR
Compensation
TimeBorrell & Gagneux 2009 IJTLD 13: 1456-66
Evolution of Drug Resistance
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Compensatory Mutations in rpoA/C
Comas et al. 2012 Nature Genetics 44: 106–110
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Comas et al. 2012 Nature Genetics 44: 106–110
In clinico Fitness of rpoA/C Mutations
High-confi. CMs
All CMs
*
*
* P < 0.05
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Song et al. 2014 Mol Microbiol 91: 1106–19
Genetics in M. smegmatis
In vitro growth Transcription efficiency
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Gygli et al. 2017 FEMS Microbiol Rev, in press.
• RIFR strains: N=1,488• + RpoA: N=73• + RpoC: N=729
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Fenner et al. AAC 2012 56: 3047-53
Mtb Lineage Impacts INH Resistance LevelsP
erce
ntag
e
0
20
40
60
80
100
MIC <3.0mg/L
MIC >3.0mg/L
MIC <3.0mg/L
MIC >3.0mg/L
0.0110.004
5
5
2
2
3
1764
24
katG 315mutations
inhA promotor-15mutations
2
2
2
3
InhA pro ‐15mutations
KatG 315mutations
MIC MIC • 134 clinical INHR isolates
0.005
Lineage 4
Lineage 3
Lineage 2
Lineage 6
Animalstrains
Lineage 5
Lineage 1
Lineage 7
100
100
100
100100
100
100
99
100100
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Positive Sign Epistasis in DoubleR
Borrell et al. 2013 Evol Med Publ Health eot003: 65-74
rpoB / gyrA mutations
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Epistasis
Drug-resistancemutation(s)
(e.g. rpoB/gyrA)
Compensatorymutations
(e.g. rpoA/C)
Strain geneticbackground
(e.g. L1 vs L2)
• Success of MDR Mtb• MICs• Patient outcome (?)
Borrell & Gagneux 2011 Clin Microbiol Infect 17: 815–820
Conclusion (1): Epistasis matters!
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A Web of Epistasis Mediates MDR in Mtb
Trauner et al. 2014 Drugs 74: 1063-72
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What about within-host evolution?
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Simple population
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Antibiotic treatment
Time
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Simple population + 1
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Antibiotic treatmentTime
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Case Study From Switzerland
• Tibetan refugee (HIV-neg.)
• Primary resistance to: isoniazid rifampicin (+ compensatory mutation in rpoC) pyrazinamid streptomycin ethionomide fluoroquinolones linezolid (!)
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“Clinical Cure” Relaps
Bloemberg et al. 2015 NEJM 373: 1986-8
Resistancemutationsto 7 drugs
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“Clinical Cure” Relaps
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
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“Clinical Cure” Relaps
capreomycinR
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
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“Clinical Cure” Relaps
capreomycinR
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
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“Clinical Cure” Relaps
delamanidR
capreomycinR
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
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“Clinical Cure” Relaps
bedaquilineR
clofazimineR
capreomycinR
delamanidR
Bloemberg et al. 2015 NEJM 373: 1986-8
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What about
other
patients? AndrejTrauner
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Mtb in the host
Rare(10)
Minor(2)
Major(1)
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Antibiotic treatment
Time
How stable are individual clones?
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time (weeks)0 2 4 6 8 16 24
P01P02P03P04P05P06P07P08P09P10P11P12 D
Non-efficacious treatmentEfficacious treatment
Treatment
PhenotypicDST
INH
RIF
EMB
STR
GenotypicDST
INJ
FQ PZA
DS DR
Context of Treatment Efficacy
Trauner et al. 2017 Genome Biol, in press.
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1 out of 12 patients.
Emergence of FQ resistance
Trauner et al. 2017 Genome Biol, in press.
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Total variable SNPs = 492
Site Frequency Spectrum
Trauner et al. 2017 Genome Biol, in press.
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Multiple isolatedpopulations
Diversity driven by drift
Purifying selectionon minor clones
Predominant clone
Trauner et al. 2017 Genome Biol, in press.
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D: Detected ND: Not detectedpD : Stable pND : AbsentpDND: Loss pNDD: Gain
Quantifying the Trajectory of Mutations
Trauner et al. 2017 Genome Biol, in press.
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Non-efficacious treatment: ALL SNPs NSY SNPs SYN SNPsEfficacious treatment: ALL SNPs NSY SNPs SYN SNPs
Trauner et al. 2017 Genome Biol, in press.
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Purifying Selection in Efficaciously Treated Patients
Trauner et al. 2017 Genome Biol, in press.
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Efficaciously treated Nonefficaciously treated
Gene set Na Excessive mutationb Excess NSYc Excessive
mutation Excess NSY
DrugResistanced
13 0/100 (0.501) 0/0 (1.000) 5/87 (0.001) 5/5 (0.177)
DrugResistanceAssociatede,f
166 10/100 (0.545) 4/10 (0.987) 6/87 (0.946) 6/6 (0.121)
MycolateSuperpathwayg
54 3/100 (0.881) 1/3 (0.964) 5/87 (0.229) 3/5 (0.876)
MTBC T-CellAntigensh
300 14/100 (0.153) 10/14 (0.426) 6/87 (0.550) 6/6 (0.121)
a Number of genes in the gene set. b Proportion of mutations in gene set, p-value calculated with a one-sided binomial test. c Proportion of NSY mutations ingeneset, p-value calculated with a one-sided binomial test. d Walker et al., e Zhang et al., f Farhat et al., g O’Neill et al., h Coscolla et al.
Non-efficaciously Treated Patients Accumulate Mutations in DR Genes
Trauner et al. 2017 Genome Biol, in press.
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• Most new mutants are unstable.
• Mutations with no (little) functional effect
are more stable.
• This is particularly true in efficaciously
treated patients.
• Non-efficaciously treated patients
accumulate mutations in DR genes.
Conclusions (2)
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Thanks to… CollaboratorsUniversity of Valencia
Iñaki Comas
New York UniversityJoel Ernst
University of Cape TownRob WilkinsonHelen Cox
Stellenbosch UniversityRob Warren
University of BernMatthias Egger
University of ZurichErik Böttger
UCSFMidori Kato-Maeda
Sanger InstituteSimon Harris
University of GhanaDorothy Yeboah-Manu
Institute Trop. Med. AntwerpBouke de Jong
Fudan UniversityQian Gao
ETH ZurichRuedi AebersoldUwe SauerTanja StadlerJörg StellingChristian Beisel
Forschunszentrum BorstelStefan Niemann
Max-Planck Institute JenaJohannes Krause
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Thanks to…
• Sonia Borrell• Mireia Coscolla• Daniela Brites• Andrej Trauner• Julia Feldmann• Miriam Reinhard• Levan Jugheli• Sebastian Gygli• Liliana Ruthaiwa• Rhastin Castro• Chloe Loiseau• Monica Ticlla• Peter Major