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Dispatch
Global Distribution of
Mycobacterium tuberculosis Spoligotypes
Ingrid Filliol,* Jeffrey R. Driscoll,† Dick van Soolingen,‡ Barry
N. Kreiswirth,§ Kristin Kremer,‡ Georges Valétudie,* Dang Duc Anh,¶ Rachael
Barlow,# Dilip Banerjee,** Pablo J. Bifani§, Karine Brudey,* Angel Cataldi,††
Robert C. Cooksey,‡‡ Debby V. Cousins,§§ Jeremy W. Dale,¶¶ Odir A. Dellagostin,##
Francis Drobniewski,*** Guido Engelmann,††† Séverine Ferdinand,* Deborah
Gascoyne-Binzi,# Max Gordon,* M. Cristina Gutierrez,‡‡‡ Walter H. Haas,§§§
Herre Heersma,‡ Gunilla Källenius,¶¶¶ Eric Kassa-Kelembho,### Tuija Koivula,¶¶¶
Ho Minh Ly,¶ Athanasios Makristathis,**** Caterina Mammina,†††† Gerald
Martin,‡‡‡‡ Peter Moström,* Igor Mokrousov,§§§§ Valérie Narbonne,¶¶¶¶
Olga Narvskaya,§§§§ Antonino Nastasi,#### Sara Ngo Niobe-Eyangoh,‡‡‡ Jean
W Pape,*****††††† Voahangy Rasolofo-Razanamparany,‡‡‡‡‡ Malin Ridell,§§§§§
M. Lucia Rossetti,¶¶¶¶¶ Fritz Stauffer,##### Philip N. Suffys,****** Howard
Takiff,†††††† Jeanne Texier-Maugein,‡‡‡‡‡‡ Véronique Vincent,‡‡‡ Jacobus
H. de Waard,§§§§§§ Christophe Sola,* and Nalin Rastogi*
*Institut Pasteur, Pointe-à-Pitre, Guadeloupe, French West Indies;
†Wadsworth Center, Albany, New York, USA; ‡National Institute of Public
Health and the Environment, Bilthoven, the Netherlands; §Public Health
Research Institute, New York, New York, USA; ¶National Institute of Hygiene
and Epidemiology, Hanoi, Vietnam; # General Infirmary, Leeds, U.K.; **St.
Georges’ Hospital Medical School, London, U.K.; ††Instituto de Biotecnologia,
Castelar, Argentina; ‡‡Centers for Disease Control and Prevention, Atlanta,
Georgia, USA; §§Australian Reference Laboratory for Bovine Tuberculosis,
Department of Agriculture, South Perth, Australia; ¶¶University of Surrey,
Guildford, Surrey, U.K.; ##Universidade Federal, Pelotas, Brazil; ***Public
Health Laboratory Service, Dulwich Hospital, London, U.K.; †††University
Children’s Hospital, Heidelberg, Germany; ‡‡‡Institut Pasteur, Paris,
France; §§§Robert Koch Institute, Berlin, Germany; ¶¶¶Swedish Institute
for Infectious Disease Control, Solna, Sweden; ###Institut Pasteur, Bangui,
Central African Republic; ****Hygiene-Institut der Universität, Wien,
Austria; ††††University of Palermo, Palermo, Italy; ‡‡‡‡Bundesinstitut
für gesundheitlichenVerbraucherschutz und Veterinärmedizin, Jena, Germany;
§§§§Pasteur Institute of Saint Petersburg, Saint Petersburg, Russia; ¶¶¶¶Centre
Hospitalier Universitaire, Brest, France; ####University of Firenze, Firenze,
Italy; *****Les Centres Gheskio, Institut National de Laboratoire et de
Recherche, Port-au- Prince, Haïti; †††††Cornell University, Ithaca, New
York, USA; ‡‡‡‡‡Institut Pasteur, Tananarive, Madagascar; §§§§§Göteborg
University, Göteborg, Sweden; ¶¶¶¶¶Universidade Federal do Rio Grande
do Sul, Brazil; #####Bundesstaatliche bakteriologisch-serologische Untersuchungsanstalt
Wien, Austria; ******Oswaldo Cruz Institute, Rio de Janeiro, Brazil; ††††††Caracas,
Venezuela; ‡‡‡‡‡‡Centre Hospitalier Universitaire, Bordeaux, France; and
§§§§§§Instituto de Investigacionas Cientificas, Caracas, Venezuela
Suggested citation for this article: Filliol
I, Driscoll JR, van Soolingen D, Kreiswith BN, Kremer K, Valétudie G,
et al. Global distribution of Mycobacterium tuberculosis spoligotypes.
Emerg Infect Dis [serial online] 2002 Nov [date cited];8. Available
from: URL: http://www.cdc.gov/ncidod/EID/vol8no11/02-0125.htm
We present a short
summary of recent observations on the global distribution of the major
clades of the Mycobacterium tuberculosis complex, the causative
agent of tuberculosis. This global distribution was defined by data-mining
of an international spoligotyping database, SpolDB3. This database contains
11,708 patterns from as many clinical isolates originating from more
than 90 countries. The 11,708 spoligotypes were clustered into 813 shared
types. A total of 1,300 orphan patterns (clinical isolates showing a
unique spoligotype) were also detected.
Since the publication of the second version of our spoligotypes database
on Mycobacterium tuberculosis (1), the causative
agent of tuberculosis (TB), the proportion of clustered isolates (shared
types [STs]) increased from 84% (2,779/3,319) to 90% (11,708/13,008).
Fifty percent of the clustered isolates were found in only 20 STs. Three
of these isolates are M. bovis, including M. bovis BCG (ST
481, 482, and 683). The addition of the next 30 most frequent STs increased
the total proportion of clustered isolates (65% instead of 50% initially).
A total of 36 potential subfamilies or subclades of M. tuberculosis
complex have been tentatively identified, leading to the definition of
major and minor visual recognition rules (Table).
The ancestral East-African Indian family (EAI) is made up of at least
five main subclades, whereas at least three major spoligotyping patterns
are found within the Haarlem family (2). Two families
found in central and Middle Eastern Asia (CAS1 and CAS2) are newly defined.
The X family (3) is also currently split into at least
three well-defined subclades. However, the subdivision of family T (T1–T4,
likely to represent relatively old genotypes), which differs from the
classic ST 53 (all spacers present except 33–36), remains poorly defined.
Similarly, the Latino-American and Mediterranean family (LAM) is tentatively
split into subclades LAM1–LAM10 (4). Spoligotyping used
alone is not well suited for studying the phylogeny of these two clades
(T and LAM). Such study will require results from other genotyping methods
such as IS6110-restriction fragment length polymorphism (5)
or mycobacterial interspersed repetitive units–variable number of DNA
tandem repeats (6). Among well-characterized major clades
of tubercle bacilli, four families represent 35% of 11,708 clustered isolates
(Beijing 11%, LAM 9.3%, Haarlem 7.5%, and the X clade 7%).
The global distribution of the most frequently observed spoligotypes
by continent in SpolDB3 is as follows. Among the patterns originating
in North America (n= 4,276, 32% of the total number of isolates in the
database), 16% of the strains are of the Beijing type, 14% belong to ST
137 or ST 119 (X family), and 8% are unique (results not shown). In Central
America (n=587, 4.5%), 8% of the strains belong to the ubiquitous ST 53,
7% are ST 50, and 6% are ST 2; the last two STs are part of the Haarlem
family. In South America (n=861, 6.6%), the distribution of ST 53 and
ST 50 accounts for 10% and 9%, respectively, of the spoligotypes, whereas
ST 42 accounts for as much as 9% of the total isolates. The origin of
ST 42 remains to be established. In Africa (n=1,432, 11%), ST 59 and ST
53 account for 9% of all isolates studied thus far; however, the values
obtained for ST 59 are biased because strains from Zimbabwe are overrepresented.
We also observed that M. africanum ST 181 accounts for as much
as 6% of all spoligotypes from Africa in our sample.
In Europe (n=4,360, 33.5%), ST 53 represents as much as 9% of the spoligotypes,
ST 50 and 47 (Haarlem family) represent 8% of the cases, and the Beijing
family accounts for 4% of the spoligotypes. In the Middle Eastern and
central Asian region, where the number of samples obtained is still very
low (n=351, 2.7%), a high diversity of strains within the EAI and CAS
families has been observed, and no single pattern currently exceeds 5%.
Further studies of isolates from these regions are needed, e.g., in India,
where our sampling is still anecdotal (n=44 isolates). Notwithstanding
the scarcity of available data from this region, the observed diversity
suggests that this region might be of great interest for further study
of the genetic variation of tubercle bacilli. Contrary to what we observed
for the Middle East and central Asia, the Far East Asian region (n=801,
6.1%) is characterized by the prevalence of a single genotype, the Beijing
type family, a family linked to emerging multiresistance (7).
One out of two strains in the Far East is a Beijing type. In Oceania (n=340,
2.6%), ST 19 and Beijing account for 15% and 13%, respectively, of clustered
isolates. Thus, this preliminary analysis of the spoligotype distribution
of SpolDB3 clearly shows major differences in the population structure
of tubercle bacilli within the eight subcontinents studied (Africa; Europe;
North America; Central America; South America; Middle East and Central
Asia; Far East Asia; and Oceania).
At present, SpolDB 3 is an experimental tool that has yet to prove its
usefulness in tracking epidemics. Nevertheless, the facility with which
matches between spoligotypes can be detected suggests that this tool may
be a good screening mechanism for population-based studies on recent TB
transmission. Indeed, the detection of a rarely found ST in SpolDB3 may
be a catalyst that signals researchers to look for the clonality of the
isolates and to study their epidemiologic relatedness.
Data-exchange protocols through inter-networking will also be implemented
in the near future. Working groups such as the European Network for Exchange
of Molecular Typing Information (available from: URL:
www.rivm.nl/enemti) are coordinating such initiatives. The expanded
use of the Bionumerics software (third upgrade; Applied Maths, St. Martens-Latem,
Belgium) may also foster this research field. SpolDB3 will also be instrumental
in facilitating better understanding of the driving forces that shape
tubercle bacilli evolution. Further research should now emphasize the
use of data-mining methods, in combination with experts’ knowledge, to
tackle the complex dynamics of the population's genetics of tubercle bacilli
and TB transmission (3). Our sample represents the compilation
of many national studies and, as such, should be considered as an ongoing
population-based project aimed at studying global TB genetic diversity.
Nevertheless, obtaining a more precise and representative snapshot of
the genetic variability of M. tuberculosis complex will require
a larger sampling. Although only partially representative of worldwide
spoligotypes of M. tuberculosis complex, Spo1DB3 contains a reservoir
of genetic information that has already proved useful for defining the
phylogenetic links that exist within the TB genomes and for constructing
theoretical models of genome evolution. Much remains to be done to evaluate
the potential of global genetic databases to better characterize casual
contacts (that could lead to identification of sporadic cases) in TB epidemiology.
An improved version of our database, which will focus on areas with a
high prevalence of TB, is currently in development; as of August 26, 2002,
it had 20,000 isolates and 3,000 alleles. Ongoing population-based genotyping
projects will likely help shed light on contemporary and ancient tubercle
bacilli’s evolutionary history.
This paper was written as part of the EU Concerted Action project QLK2-CT-2000-00630
and partly supported by the Réseau International des Instituts Pasteur
et Instituts Associés, Institut Pasteur and Fondation Française Raoul
Follereau, France. An electronic, simplified, version of SpolDB3 is available
from the corresponding authors upon request.
Dr. Filliol performed this work as part of her doctoral thesis. She has
been working at the Institut Pasteur de Guadeloupe for the last 4 years.
Her research focuses on molecular epidemiology and phylogeny of tubercle
bacilli.
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