SEH Evolution TB

8/2/2019 SEH Evolution TB

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Bio 101 Lecture

by

Seyed E. Hasnain

Evolution of Pathogenic Bacteria:Mycobacterium tuberculosis example


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Why study Pathogen Evolution?

pathogengenome

diversity


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The composition of the prokaryotic genome. Bacterial genomes consist of a

conserved core gene pool and a variable flexible gene pool.The latter consists of accessory and mobile genetic elements

(modified after Morschhuser et al., 2000).


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4

MicroevolutionMicroevolution

Development of organisms in days and weeks

MacroevolutionMacroevolution

Development of species and variants in longterm intervals


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5

MicroMicro--

evolutionevolution

Point mutationsGene expression,

Modulation

Plasmid,Phage transfer

Horizontalgene transfer

Phase, AntigenicVariation

Geneticrearrangements

DeletionsGenome reduction,Deletions

MacroMacro--

evolutionevolution

PAI development

Developmentof new

variants

Development ofintracellularpathogens

Pathoadaptation

GeneticGenetic

mechanismmechanism


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6

WhyM. tuberculosis


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US 37.7%

Latin America 17.7%

Africa 9.6%

Asia 33.3%

Europe 2.1%

The morbidity and mortality statistics of TB is soextravagant that in the world someone dies of TB

every 15 seconds (WHO Report 2003 )

The Ticking Time Bomb

TB Growth Rate - 2001


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Infection 9 Million cases/ yearDeath 2 Million cases / year

2 Billion people are infectedin world

Special Feature: Tuberculosis: Nature Medicine :March 2007

Global Scenario of TB


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Magnitude of TB in India

40% of the Indian population is infected with the TB bacillus.

Every day, more than 20,000 people become infected with the TB

bacillus and about 5000 develop the disease.

Every year 18 lakh (or 1.8 million) people inIndia develop TB, of which nearly 8 lakh

(0.8 million) are infectious (sputum-positive).

Untreated pulmonary TB cases spread infection to others in thecommunityeach infectious patient can infect 10-15 persons in ayear unless effectively treated.

Despite being completely curable, TB claims the

lives of >400,000 people in India every year

RNTPC report 2004


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Tuberc u los is in hum ans

INTRACELLULAR pathogen (facultative extra cellular)

Exposed Infected(2 billion, 8million new cases

per year)

Primary

TB

Latent

TBReactivation

30%

80-90%

5-10%

5-10%

Clearance

70%

Death

(2 million)


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Problems of interventions against TBLack of Epidemiological Data

Several genes with unknown function

Problems of Moon lighting

Persistence and Immune Evasion

Poor understanding of the pathogen-host-environment triangle

Emergence of MDR/XDR

Emergence of TB-IRIS

Emergence of TB-Diabetes synergy

Absence of Good Diagnostics: Tuberculin skin test >125 y

No new drug for the past 4 decades: 6 months MDT regime

No new vaccine (BCG : 75 y; M indicus pranii, a ray of hope)

No bio-marker for total sterilization


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Two major paradigms govern evolution of persistent

bacteria

Mycobacteria

Helicobacters

Emergence of specialist lineages

Optimization of fitness

Vertical Genome Reduction

Lateral Genome Acquisition

Ahmed et al., 2008 Nature Rev Microbiol6:387-394


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Evolution of GenomesEvolution of Genomes

Gene acquisition

Prophages

Plasmids

PAIs,Genomic islands (GEIs)Tn, IS, Islets,Integrons

TransformationTransduction

Conjugation

EvolvedGenome

RearrangementsMutations

Deletions

Genome reduction


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Genetic changes accumulate in the genome as a repertoire of

gene acquisition and loss, on an evolutionary time-scale

Many human pathogens have such changes ascribed to rigorous

selection against the host defenses and adaptation to different niches

Genome wide analysis of such a repertoire in pathogens with

different bio-geo-climatic history is a term coined by us as

GEOGRAPHIC GENOMICS

Geographic evolution:The concept of Geographic

Genomics

Majeed et al., Bioinformatics 2004

Hasnain and Ahmed LANCET Infect Dis 2004


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Common ancestor M. leprae

M. canettii

RD9

TbD1

RD8 RD7

RD seal

RD12

RD14

M. tuberculosis (ancestral)

M. tuberculosis (modern)

M. africanumM. africanum

M. pinnipedae

M. microti

M. bovis

M. caprae

M. bovis BCG

decay (pseudogenization)

RD10

RD13

RD4

RD1

RD2

RD can

RD Mic

Reductional polymorphisms are the only major source of lineage diversity

in pathogenic Mycobacteria

Genotype diversity is otherwise minimum, within the same geographical region


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Reductive Evolution of the Mtb Complex genome

Brosch et al., 2002

Ge nom

e

Ge nom

e

s i z e

s iz e

Hostspec

ificity

Hostspec

ificity

Effectivei

nvasion

Effectivei

nvasion

Survival

Survival


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Genomic Features of Ancient strains

1. Fewer than 6 copies of IS6110

2. Specific signature at MIRU Locus 4

3. Principle genetic group 1

4. Typical spoligotype

5. TbD1 region is intact


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spoligotype

isolateno.

origin

PGG

TbD1

MIRU-VNTRMIRU-VNTR dendrogram

EAI

Delhi/CAS

W/Beijing

LAM

T

X

Miru02

VNTR424

VNTR577

Miru04

Miru40

Miru10

Miru16

VNTR1895

Miru20

VNTR2347

VNTR2401

VNTR2461

Miru23

Miru24

Miru26

Miru27

VNTR3171

Miru31

VNTR3690

VNTR4156

Miru39

Single, Double, Triple

Ancestral (40%)

Delhi (25%)

Beijing (8-10%)

Others (15-20%)


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TbD1 region is present in about 36% isolates - ancient features

Ahmed et al. J Clin Microbiol.2004 42:3240-

3247

TbD1/Rd9 analysis in the Indian isolates

Q


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Do ancestral lineages ofMycobacterium tuberculosis predominate in

India

If yes, does this denotes an ancient focus oftuberculosis in South Asia?

Does this provide any advantage for TB management in India?


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I solates from South I ndia have been described t o be of low virulenceand less disseminat ing?

A careful compar ison of t he virulence propert ies of ancient TbD1+st rains w it h t hose of t he more modern strains, using t he variety of

animal models current ly available, may thus provide novel insightsint o the evolut ionary dynamics of t his maj or pathogen.

Analysis of samples recovered from Egypt ian m ummies

suggest s t hat t he modern lineages of M. tuberculosisdiverged f romthe TbD1+ lineage thousands of years ago. Ancient Hindu script ures

also suppor t t he cont ent ion t hat t his disease has been present asearly as 10, 000 BC in I ndia.

Therefore, t he predominance of ancest ral strains and the relat ively poorrepresent ation of t he most recent lineages in I ndia, as apparent fromthis study, are consistent w it h t he hypothesis t hat I ndia is a historically

ancient focus of t uberculosis.

Gut ierrez + Ahmed et al., 2006 Emerging I nfect Dis


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Mycobacterium w genome program

Immune related disorders or infections are a result of changing lifestylesand thereby reduced exposure to certain bacteria that have been intricatelyassociated as "old friends" during most of the mammalian evolution.

A very important group of bacteria among these organisms, are saprophyticmycobacteria, which are recognized by the innate immune system asbiologically harmless. It is hypothesized that these "old friends" might bemaintaining levels of regulatory immune cell populations (Rook et al., 2004),such as the cytokine secreting and antigen-presenting cells which are

compromised in some allergies (asthma) and chronic infectious diseases(Crohn's disease due to M. aviumcomplex).

These concepts are heralding the development of novel probiotic orimmunomodulatory therapies for lifestyle diseases based on harmlessorganisms or their components.

One such old friend is Mw !


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Ahmed N et al.,

2007 PLoS ONE

Evolu t ion of Mycobact erial Specialist s

and Generalist s


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India is saved of the TB-time bomb (unlike South Africa)

despite ~5.7 Million HIV casesWhy treatment success reaching ~90%? (Compare -> Russia=58%)Why no institutionalized outbreaks? (Compare -> Kwazulu Natal, SA)

India Russia

Bestowed with ancestral strains Crippled with Beijing strains

Source: WHO Report on TB, 2006, 2007 and 2008

India China RussiaOf new TB cases, % MDR-TB 2.8 4.0

13Of previously treated TB cases, % MDR-TB 17 26 49

India China RussiaOf new TB cases, % MDR-TB 2.8 4.0

13Of previously treated TB cases, % MDR-TB 17 26 49

Ancest ral st rains - Old is Gold?


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OLD is GOLD : I ssues t o ponder

1. Ancest ral l ineages are w idespread and perhaps do not al lowspread of other genogroups

Host adaptation?Preferent ial colonizat ion?Host Genet ic resistance?

2. Are ancest ral str ains really advantageous for t heTB cont rol Program?

Slow disseminat ing t ypes?Are t hese protect ive: Super in fect ion?Are t hey less virulent : Less MDR/ XDR?Are they more cooperat ive: I nfect ionburden vs Disease burden?

3. How long t his advantage sustains?Diabetes, HI V, Beij ing, LAM

Ahmed et-al Inf Gen Evol 2009


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Study of Evolut ionary

Dynamics and MolecularEpidemiology not only perm it st racking of a pathogen but

also enables t he ident if icat ionof new ant igens of diagnost ic

potent ial and also possibledrug t arget s


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Humans and microbes are not at war.Rather, both parties are engaged inamoral, self interested, co-evolutionary

struggle.We need to understand better, and

therefore anticipate, thedynamics of that process

and Until we Understand These Processes Mtb willContinue to Challenge Human Intelligence!!

A J McMichael. Phil. Trans. R. Soc. Lond. B (2004) 359, 10491058

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SEH Evolution TB