Evolution of Pathogenic Bacteria: Mycobacterium tuberculosis example

Bio 101 Lecture

by

Seyed E. Hasnain

Why study Pathogen Evolution?

pathogen genome diversity

2000).The composition of the prokaryotic genome. The latter consists of accessory and mobile genetic elements (modified after Morschhäuser et al.. Bacterial genomes consist of a conserved “core gene pool” and a variable “flexible gene pool”. .

Microevolution Development of organisms in days and weeks Macroevolution Development of species and variants in long term intervals 4 .

Antigenic Variation Development of new variants Pathoadaptation 5 Point mutations Gene expression. Phage transfer Macroevolution PAI development Genome reduction.Genetic mechanism Horizontal gene transfer Microevolution Plasmid. Deletions Deletions Development of intracellular pathogens Genetic rearrangements Phase. Modulation .

tuberculosis 6 .Why M.

‘The Ticking Time Bomb’ The morbidity and mortality statistics of TB is so extravagant that in the world someone dies of TB every 15 seconds (WHO Report 2003 ) Europe 2.7% Asia 33.7% 7 TB Growth Rate .3% Africa 9.6% Latin America 17.2001 .1% US 37.

Global Scenario of TB Infection 9 Million cases/ year Death 2 Million cases / year 2 Billion people are infected in world Special Feature: Tuberculosis: Nature Medicine : March 2007 8 .

more than 20.Despite being completely curable.8 million) people in India develop TB.000 people become infected with the TB bacillus and about 5000 develop the disease.8 million) are infectious (sputum-positive).000 people in India every year Magnitude of TB in India 40% of the Indian population is infected with the TB bacillus. TB claims the lives of >400. Untreated pulmonary TB cases spread infection to others in the community—each infectious patient can infect 10-15 persons in a year unless effectively treated. Every day. RNTPC report 2004 9 . Every year 18 lakh (or 1. of which nearly 8 lakh (0.

Tuberculosis in humans INTRACELLULAR pathogen (facultative extra cellular) Primary TB Latent TB 5-10% Death (2 million) 5-10% 30% Infected (2 billion. 8 million new cases per year) Exposed 70% 80-90% Reactivation Clearance .

M indicus pranii.Problems of interventions against TB Lack 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. a ray of hope) No bio-marker for total sterilization .

Two major paradigms govern evolution of persistent bacteria Lateral Genome Acquisition Helicobacters Optimization of fitness Vertical Genome Reduction Mycobacteria Emergence of ‘specialist’ lineages Ahmed et al. 2008 Nature Rev Microbiol 6:387-394 ..

„Islets“.Evolution of Genomes Gene acquisition Transformation Transduction Conjugation Plasmids PAIs. IS. Genomic islands (GEIs) Tn.Integrons Prophages Rearrangements Mutations Deletions Evolved Genome Genome reduction 13 .

Bioinformatics 2004 Hasnain and Ahmed LANCET Infect Dis 2004 . 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” Majeed et al..Geographic evolution: The concept of Geographic Genomics • Genetic changes accumulate in the genome as a repertoire of gene acquisition and loss.

africanum M. microti M. canettii M. bovis RD1 RD2 RD14 Genotype diversity is otherwise minimum. africanum M. tuberculosis (modern) RD7 RD seal RD12 RD13 RD Mic M. caprae RD4 M.Reductional polymorphisms are the only major source of lineage diversity in pathogenic Mycobacteria M. bovis BCG . within the same geographical region M. leprae M. pinnipedae M. tuberculosis (ancestral) RD can TbD1 decay (pseudogenization) Common ancestor RD10 RD8 RD9 M.

. 2002 .Reductive Evolution of the Mtb Complex genome •Host specificity •Effective invasion •Survival Genome size Brosch et al.

Typical spoligotype 5.Genomic Features of Ancient strains 1. Specific signature at MIRU Locus 4 3. Principle genetic group 1 4. Fewer than 6 copies of IS6110 2. TbD1 region is ‘intact’ 17 .

X LAMW/Beijing Delhi/CAS MIRU-VNTR dendrogram T EAI spoligotype Miru 02 VNTR 424 VNTR 577 Miru 04 Miru 40 Miru 10 Miru 16 VNTR1895 Delhi (25%) Beijing (8-10%) Ancestral (40%) Others (15-20%) Single. Double. origin PGG TbD1 . Triple Miru 20 VNTR2347 VNTR2401 MIRU-VNTR VNTR2461 Miru 23 Miru 24 Miru 26 Miru 27 VNTR3171 Miru 31 VNTR3690 VNTR4156 Miru 39 isolate no.

2004 42:32403247 .TbD1/Rd9 analysis in the Indian isolates TbD1 region is present in about 36% isolates .ancient features Q Ahmed et al. J Clin Microbiol.

Do ‘ancestral’ lineages of Mycobacterium tuberculosis predominate in India If yes. does this denotes an ancient focus of tuberculosis in South Asia? Does this provide any advantage for TB management in India? .

Therefore. the predominance of ancestral strains and the relatively poor representation of the most recent lineages in India. are consistent with the hypothesis that India is a historically ancient focus of tuberculosis. Gutierrez + Ahmed et al. Ancient Hindu scriptures also support the contention that this disease has been present as early as 10. may thus provide novel insights into the evolutionary dynamics of this major pathogen. Isolates from South India have been described to be of low virulence and less disseminating? A careful comparison of the virulence properties of ancient TbD1+ strains with those of the more modern strains. tuberculosis diverged from the TbD1+ lineage thousands of years ago.Analysis of samples recovered from Egyptian mummies suggests that the modern lineages of M. 2006 Emerging Infect Dis . as apparent from this study.. 000 BC in India. using the variety of animal models currently available.

One such ‘old friend’ is Mw ! . which are recognized by the innate immune system as biologically harmless.. It is hypothesized that these "old friends" might be maintaining levels of regulatory immune cell populations (Rook et al. 2004). are saprophytic mycobacteria. 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. These concepts are heralding the development of novel probiotic or immunomodulatory therapies for lifestyle diseases based on harmless organisms or their components. A very important group of bacteria among these organisms.Mycobacterium w genome program Immune related disorders or infections are a result of changing lifestyles and thereby reduced exposure to certain bacteria that have been intricately associated as "old friends" during most of the mammalian evolution. avium complex).

Ahmed N et al. 2007 PLoS ONE Evolution of Mycobacterial ‘Specialists’ and ‘Generalists’ ..

% MDR-TB China 2.7 Million HIV cases Why treatment success reaching ~90%? (Compare -> Russia=58%) Why no institutionalized outbreaks? (Compare -> Kwazulu Natal.8 26 Russia 4. % MDR-TB 13 Of previously treated TB cases.0 49 17 India is saved of the TB-time bomb (unlike South Africa) despite ~5. SA) India Russia Bestowed with ancestral strains Crippled with Beijing strains Source: WHO Report on TB.Ancestral strains .Old is Gold? India Of new TB cases. 2006. 2007 and 2008 .

Are ancestral strains really advantageous for the TB control Program? Slow disseminating types? Are these protective: Super infection? Are they less virulent: Less MDR/XDR? Are they more ‘cooperative’: Infection burden vs Disease burden? 3. Ancestral lineages are widespread and perhaps do not allow spread of other genogroups Host adaptation? Preferential colonization? Host Genetic resistance? 2. Beijing. LAM Ahmed et-al Inf Gen Evol 2009 . HIV.“OLD is GOLD”: Issues to ponder 1. How long this advantage sustains? Diabetes.

Study of Evolutionary Dynamics and Molecular Epidemiology not only permits tracking of a pathogen but also enables the identification of new antigens of diagnostic potential and also possible drug targets .

Phil. Lond. Rather. 1049–1058 …and Until we Understand These Processes Mtb will Continue to Challenge Human Intelligence!! .“Humans and microbes are not ‘at war’. Soc. B (2004) 359. R. and therefore anticipate. co-evolutionary struggle. both parties are engaged in amoral. We need to understand better. the dynamics of that process” A J McMichael. Trans. self interested.

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