seh evolution tb
TRANSCRIPT
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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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MicroevolutionMicroevolution
Development of organisms in days and weeks
MacroevolutionMacroevolution
Development of species and variants in longterm intervals
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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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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