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2 Indian Journal of Medical Microbiology, (2007) 25 (1):2-3
GENETIC DIVERSITY OF PATHOGENIC MICROORGANISMS AND ITS MEDICAL AND PUBLIC HEALTH SIGNIFICANCE *JS Virdi, P Gulati, M Pai
In the last decade or so, significant amounts of data have been generated on genetic diversity of a number of pathogens. This has been accomplished largely due to the development of genotyping techniques such as multilocus enzyme electrophoresis, restriction fragment length polymorphism, random amplified polymorphic DNA, pulse field gel electrophoresis, repetitive sequence-based polymerase chain reaction, multilocus sequence typing and DNA sequencing. Why is the study of genetic diversity important and what can it contribute to medicine and public health? Several observations of both fundamental and applied nature have been gleaned from studies on diversity. Thanks to these studies, we now understand that although pathogenic microbes constitute a small proportion of all microbial species, many are characterized by high genetic diversity. For example organisms such as the HIV and influenza virus mutate extensively and pose major challenges to disease control. Further, such studies have dispelled the notion of clonal nature of pathogens. We now realize that population structures of pathogenic microbes range from effectively panmictic to strictly clonal.1 Therefore, a better understanding of genetic diversity of pathogenic microorganisms may allow us to devise public health interventions that may be more effective.2
of genetic diversity data has been the development of diagnostics, therapeutics and vaccines. Poorly understood diversity of a pathogen can lead to development of diagnostics that cannot detect the entire set of pathogen genotypes causing a particular disease. For example, the discovery of highly divergent strains of human immunodeficiency virus (HIV) that were not reliably detected by a number of commonly used diagnostic kits emphasized the need for studies to type HIV variants. Another example is the development of new tests for the detection of tuberculosis infection. Comparative genomics has allowed the identification of genomic segments (e.g., region of difference (RD1)) that are present in Mycobacterium tuberculosis but deleted from Mycobacterium bovis BCG sub-strains. Antigens encoded by such regions (e.g., ESAT-6) are currently being used in novel, blood-based interferon-gamma assays and these assays have been shown to be more specific than the tuberculin skin test.3 Also, to develop more effective therapeutics and vaccines, it is imperative that the candidate drugs/vaccines are evaluated against a set of carefully selected genotypes, which are representative of the pathogen population. 4 Vaccine development for influenza is a classic illustration.
m rf o d ns a lo tio n w lica o d ub e rf e w P m). r fo kno .co le ed ow b n la M Indkaddition i to the medical and public health implications, a capitalized y v e The field of molecular epidemiology has greatly the long-term benefits may accrue from the study of b mpathogen diversity includewhichunderstanding a of pathogens. on the knowledge gained from genetic diversity of the evolution and is teofdstrains.w. emergence of new pathogens, pathogenicity The core of molecular epidemiology is genotyping per se and s This has been particularly useful in studying global phylogenetics. As the oldest inhabitants of the earth, F w o epidemiology of pathogens and their transmission dynamics. microbes have a highly chequered history of evolution. D h (wlarge Comparative genomics of pathogens associated with human, The long-term spread of P the pathogens over e have been animal and plant hosts may reveal insights into how t geographical areas encompassing continents s i i s of their genetic pathogens evolved. Our recent understanding of the tracked because we have h databases fingerprints. Genetic T diversity a studies have been useful in emergence of human pathogens like Yersinia pestis from Y. 5
identifying the sources of outbreaks. Such studies have also helped resolve unequivocally whether the recurrence of an infectious disease is due to relapse caused by the same strain or re-infection of the host by a new strain. In addition to molecular epidemiology, a major application *Corresponding author (email: ) Microbial Pathogenicity Laboratory (JSV, PG), Department of Microbiology, University of Delhi South Campus, Benito Juarez Road, New Delhi - 110 021, India; and Division of Epidemiology and Biostatistics (MP), McGill University, Montreal, Canada Received : 15-11-06 Accepted : 09-12-06
pseudotuberculosis has been possible only with the study of large number of genetic variants of these pathogens.6 However, genetic diversity studies have been constrained by certain problems. Among these, problems associated with adequate sample selection are paramount. An appropriate sample of the pathogen population is a prerequisite for genetic diversity studies. Presently most studies rely on isolates of a pathogen obtained from culture collection (e.g., referral) centers. Such centers, however, may not represent actual diversity extant in nature, as majority of the strains in such collections are obtained from clinical settings and thus, biased towards the highly pathogenic strains with the exclusion of the opportunistic and accidental pathogenic forms. This
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Virdi et al - Genetic Diversity of Microorganisms
problem must be overcome by undertaking structured sampling schemes.7 Another concern is the lack of foolproof genotyping methods that are highly accurate in distinguishing between strains. The development of the multilocus sequence typing (MLST) method in recent years has raised hopes in this regard. 8 The sequence data obtained using MLST is reproducible and highly portable among laboratories, allowing development of global databases easily available on the internet so that global comparisons can be made. Lack of a good framework for interpretation of genetic diversity data is another stumbling block in our understanding of pathogen diversity. There is a need for standardized, international guidelines on the interpretation of genetic and molecular diversity data. Lastly, the ability of the host immune system to select certain genotypes also impacts significantly on the genetic diversity of pathogens.
Acknowledgement Supported in part by funding from the Department of Biotechnology (DBT), Department of Science and Technology (DST), Ministry of Environment and Forests (MEF), Defense Research and Development Organisation (DRDO) and the Indian Council of Medical Research (ICMR). References 1. Spratt BG, Maiden MC. Bacterial population genetics, evolution and epidemiology. Phil Trans R Soc London B Biol Sci 1999;354:701-10. 2. Read AF, Taylor LH. The ecology of genetically diverse infections. Science 2001;292:1099-102.
m o fr d ns How has India contributed to the study of genetic a diversity? In the past decade, genetic diversity studies on o tio l selected pathogens have been reported from India. These n a include Vibrio cholerae, M. tuberculosis, Helicobacter w c i pylori, Yersinia enterocolitica, Leptospira and viruses such o l d ub as rotaviruses, poliovirus and hepatitis. Genetic diversity data e pertaining to these pathogens and others isolated from India . P e ) has been reviewed recently. However, not much data are r f w m available on other important pathogens such as HIV, Neisseria r o co meningitidis, Streptococcus pneumoniae, S. pyogenes and afo n . host of enteropathogenic Escherichia coli. Similarly, genetic k e w l d diversity data on parasitic protozoa and fungal pathogens are b e no lacking. Thus, this area needs further impetus, as developing a l M dk i hitherto countries including India are a source of rich, a y e untapped, microbial diversity. Research in thisvfield requires b a not only adequate funding and training opportunities but also m dexperts. . s and collaborations with international organizations e i t w Overall, in this exciting era of genomics, the study of genetic s F w diversity of pathogens has the potential to contribute D ho (wgreatly in our fight against the diseaseP causing microbes. s site i Th a 9
Pai M. Alternatives to the tuberculin skin test: Interferon-γ
assays in the diagnosis of Mycobacterium tuberculosis infection.
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Dykhuizen DE, Polin DS, Dunn JJ, Wilske B, Preac-Mursic V, Dattwyler RJ, et al. Borrelia burgdorferi is clonal: Implications for taxonomy and vaccine development. Proc Natl Acad Sci USA 1993;90:10163-7.
Dobrindt U, Hacker J. Whole genome plasticity in pathogenic bacteria. Curr Opin Microbiol 2001;4:550-7.
Achtman M, Zurth K, Morelli G, Torrea G, Guiyoule A, Carniel E. Yersinia pestis, the cause of plague, is a recently emerged clone of Yersinia pseudotuberculosis. Proc Natl Acad Sci USA 1999;96:14043-8.
7. Gupta S, Maiden MC. Exploring the evolution of diversity in pathogen populations. Trends Microbiol 2001;9:181-5.
Maiden MC, Bygraves JA, Feil E, Morelli G, Russell JE, Urwin R, et al. Multilocus sequence typing: A portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci USA 1998;95:3140-5.
Virdi JS, Sachdeva P. Genetic diversity of pathogenic microorganisms – Basic insights, public health implications and the Indian initiatives. Curr Sci 2005;89:113-23.
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