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Previous Article | Next Article 
Journal of Clinical Microbiology, October 1998, p. 3099-3102, Vol. 36, No. 10
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Molecular Fingerprinting of Mycobacterium tuberculosis
Isolates Obtained in Havana, Cuba, by IS6110 Restriction
Fragment Length Polymorphism Analysis and by the
Double-Repetitive-Element PCR Method
Ernesto
Montoro,1
José
Valdivia,1 and
Sylvia Cardoso
Leão2,*
Instituto de Medicina Tropical Pedro
Kourí, Havana, Cuba,1 and
Departamento de Microbiologia, Imunologia, e Parasitologia,
Universidade Federal de São Paulo
Escola Paulista de
Medicina, São Paulo, Brazil2
Received 19 March 1998/Returned for modification 30 May
1998/Accepted 1 July 1998
 |
ABSTRACT |
Mycobacterium tuberculosis sputum isolates from 38 patients, obtained in the first 6 months of 1997 in Havana, Cuba, were characterized by IS6110 restriction fragment length
polymorphism (RFLP) analysis and the double-repetitive-element PCR
(DRE-PCR) method. Among 41 strains from 38 patients, 24 and 25 unique
patterns, and 5 and 4 cluster patterns, were found by the RFLP and
DRE-PCR methods, respectively. Patients within two of these clusters
were found to be epidemiologically related, while no relation was
observed in patients in the other clusters. The DRE-PCR method is
rapid, and it was as discriminating as IS6110 RFLP analysis
in identifying an epidemiological association. Its simplicity makes the
technique accessible for subtyping of M. tuberculosis
strains in laboratories not equipped to perform RFLP analysis.
| |
TEXT |
The World Health
Organization-International Union against Tuberculosis and Lung
Disease Global Surveillance Project on Drug Resistance in Tuberculosis
reported that in 1996 Cuba, with a population of 11,005,866 inhabitants, had a tuberculosis incidence rate of 14.34 per 100,000. In
that year, 835 sputum smear-positive cases were reported, representing
65% of all pulmonary cases and a case detection rate of 84%. The
human immunodeficiency virus coinfection rate was 1.3%
(25).
Cuba has a tuberculosis control program, established in
1962, and short-course chemotherapy is used in 100% of cases. An
important consideration for the evaluation of tuberculosis control
programs and for infection control in nosocomial and other
institutional settings housing tuberculosis patients is the improved
understanding of the transmission of the disease due to accurate
epidemiological studies. Recent characterizations of biological markers
for typing strains have greatly facilitated and improved the study of
the epidemiology of infectious diseases (20). Molecular
techniques are used to track specific strains of pathogens and to
determine more precisely the distribution of infectious diseases in
populations, providing opportunities for more-effective interventions.
In the past, evidence for recent active transmission of tuberculosis
was based on outbreaks, on the appearance of strains showing the same
drug susceptibility pattern, on conversion of tuberculin test results
after contact with a tuberculosis patient, or on phenotypic methods
such as phagotyping, serotyping, biotyping, and electrophoretic
analysis of enzymes (7). The utilization of phenotypic
markers requires 4 to 8 weeks of growth of Mycobacterium tuberculosis, and such studies have been limited due to the
lack of sufficiently discriminating polymorphic markers able to
distinguish the various bacilli infecting unrelated individuals
(17). Until recently, the only method available for typing
of M. tuberculosis strains was phage typing (2).
However, this method has been used by few laboratories, due to the
difficulty of the technique and the fact that only a limited number of
mycobacteriophage types were recognized.
Recent advances in molecular biology have led to the use of molecular
techniques, which are based on the principle that there are phenotypic
or genotypic differences from strain to strain but not within a given
strain (20). Genotypic fingerprinting utilizes slight
differences in the total chromosome that are generally not related to
phenotypic differences.
Restriction fragment length polymorphism (RFLP) analysis using the
repetitive DNA element IS6110 in M. tuberculosis
has been a powerful tool for confirming the results of standard
epidemiological investigations (22). Pulsed-field gel
electrophoresis (21) and different methods of strain typing
by PCR, including double-repetitive-element PCR (DRE-PCR)
(6), randomly amplified polymorphic DNA analysis (10), mixed-linker PCR (8), spoligotyping
(12), and others, have also been reported. Many examples of
epidemiologic studies illustrate the utility of these molecular
techniques: the study of tuberculosis outbreaks in institutional
settings, such as prisons, hospitals, and shelters (4, 5,
18), and in community settings, as in Switzerland
(7), San Francisco (13), and New York (1, 6); studies in specific geographic areas to trace the migration of strains around the world (22, 26); studies to demonstrate occupational exposure among health care personnel
(19); and studies of laboratory contamination
(14). In most of these studies, IS6110-based RFLP
analysis has been used.
However, laboratory methods for the identification of biological
markers need to be simplified in order to increase their accessibility
for clinical laboratories in both developed and developing countries.
The DRE-PCR method is based on PCR amplification of segments located
between two repetitive sequences from the M. tuberculosis genome: IS6110 and the polymorphic GC-rich
repetitive sequence (6). This is a rapid subtyping method
that can be performed with the primary growth of M. tuberculosis, eliminating the need to subculture. In the original
paper (6) it has been shown to be as discriminative as the
IS6110 RFLP method. In this study we compared the DRE-PCR
method with the IS6110 RFLP method with regard to
their abilities to predict epidemiological relationships among
clinical strains of M. tuberculosis isolated in
Havana, Cuba, in 1997.
Between January and July of 1997, 41 strains were isolated from sputum
samples from 38 patients at the Instituto Pedro Kourí (IPK) in
Havana. They represent consecutively obtained strains that have
been isolated in the area, including nine isolates from an active
surveillance study performed in correctional institutions in Havana.
The samples were examined by microscopy after Ziehl-Neelsen staining and cultured in Lowenstein-Jensen medium.
Identification and susceptibility testing were performed
according to methods described in references 9 and
3, respectively. No resistance to rifampin,
isoniazid, streptomycin, pyrazinamide, or ethambutol was observed. The
patients were tested for human immunodeficiency virus infection, and
all results were negative.
IS6110 RFLP analysis.
DNA fingerprinting was
carried out by the standardized protocol of van Embden et al.
(23). Briefly, genomic DNA was isolated and digested with
PvuII (Gibco/BRL, Rockville, Md.), electrophoresed on an
0.8% agarose gel, and vacuum blotted onto nylon membranes (Hybond N+;
Amersham, Little Chalfont, Buckinghamshire, United Kingdom).
A mixture of lambda-HindIII and
X174-HaeIII (Gibco/BRL) was used as an external
marker. No internal standards were used. Southern blotting was
performed with a PCR-generated probe amplified from M. tuberculosis H37Rv DNA with the primers INS-1 and INS-2 (23). Labeling and detection were performed with the ECL
Direct System (Amersham). Comparison of fingerprints was
performed visually. Two or more isolates with identical RFLP
patterns or with patterns differing in only one band were considered to
belong to a cluster and possibly to be epidemiologically related. The
subgroup of clustered strains was subjected to a second RFLP
analysis, and the patterns were analyzed with GelCompare software
(Applied Maths, Kortrijk, Belgium) (Fig.
1).
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|
FIG. 1.
RFLP patterns from the strains showing similar or
identical patterns by visual inspection. The RFLP patterns were
analyzed and normalized by using GelCompare software. Cluster I
comprises strains 9, 12, 16, 28, 38, 14, and 40; cluster II, strains 3, 7, 8, and 20; cluster III, strains 31 and 24; cluster IV, strains 1 and
13; and cluster V, strains 37 and 36. Mt, M. tuberculosis
MT14323 reference strain. Strain 22 was not included in cluster III,
despite pattern similarity, because it differs in more than one band.
|
|
Two to sixteen copies of IS6110 were found in each of the
Cuban M. tuberculosis isolates, and 29 different patterns
were observed. Of these, 17 strains were included in five cluster
patterns (Fig. 1). Cluster I comprised seven strains from seven young
incarcerated males, aged 18 to 33 years, whose tuberculosis cases were
detected in an active surveillance investigation. Their RFLP patterns
were identical and showed 9 bands in all (Fig. 1), except for one
strain (strain 14) that had 10 bands. Cluster II showed three very
similar patterns of 11 bands: a shift in one band in strain 3 (pattern IIa) was observed in strains 7 and 20 (IIb), and a shift in a different band in strain 3 pattern was observed in strain 8 (IIc) (Fig.
1). The patients, a female of 28 and three males of 40, 50, and 70 years, respectively, had no recognized epidemiological relationships
and were diagnosed in different regions of Havana. Cluster III
showed an identical nine-band pattern in strains from two young
males imprisoned in the same institution as the patients in cluster I. The RFLP patterns of clusters I and III were unrelated. Another
identical pattern was observed in strains from two young men who
apparently were not epidemiologically related; these two strains
constituted Cluster IV. Cluster V comprised two strains obtained
from apparently unrelated patients, a young male and an old female
diagnosed in different districts of Havana.
Identical or highly related patterns were found much more
frequently in younger patients than in older patients. The mean age of patients with cluster pattern strains was 36.3 ± 16.2 years, while the mean age of patients with unrelated strains
was 56.5 ± 20.6 years. Men were found to be infected by related
or identical strains more often than women (15 men and 2 women). This
observation was not related to the number of cluster pattern strains
obtained from imprisoned male patients in the surveillance study.
DRE-PCR.
The procedure reported by Friedman et al.
(6) was slightly modified (11a). Briefly, a
loopful of each culture on a Lowenstein-Jensen slant was diluted in 1 ml of distilled water and boiled for 10 min with no further DNA
purification. The PCR amplification mixture contained 20 mM Tris (pH
8.8)-50 mM KCl (1× reaction buffer; Gibco/BRL), 2.5 mM
MgCl2 (Gibco), 200 µM each deoxynucleoside triphosphate (Gibco), 6% dimethyl sulfoxide, 50 pmol of each of the four primers, and 1 U of Taq polymerase (Gibco). The primers and their
sequences are described in reference 6. Ten
microliters of DNA solution was used in the reaction. The PCR mixture
was subjected to denaturation at 95°C for 10 min, followed by 30 cycles of denaturation at 94°C for 1 min, primer annealing at 56°C
for 2 min, and primer extension at 72°C for 3 min. The amplification
products were analyzed by electrophoresis in 2% agarose gels stained
with ethidium bromide and visualized under UV light (Fig.
2). The modifications introduced were the
inclusion of 6% dimethyl sulfoxide in the reaction mixture and the
extension step of 3 min.
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[in a new window]
|
FIG. 2.
DRE-PCR patterns of strains from the 38 patients in this
study. Numbers correspond to the sample numbers listed in Table 1. M,
1-kb DNA ladder (Gibco).
|
|
Thirty different DRE-PCR patterns were obtained, and four clusters were
observed. Cluster I comprised the strains of the seven young imprisoned
male patients. One strain showed a single-band difference (the same
strain that showed a band difference by RFLP analysis). Cluster II was
a pattern observed in four strains, one of which showed a one-band
difference. Cluster III contained two strains, one showing an extra
band. Cluster IV comprised two strains.
The patterns generated by the DRE-PCR method were compared to the
IS6110 RFLP patterns (Table
1). With the RFLP method, 29 distinct
banding patterns were observed among 41 isolates from 38 patients. Five of these were cluster patterns that included 17 patients
(45% of the patients). The DRE-PCR method produced 30 different
patterns among 38 unique isolates. Four were cluster patterns that
included 15 patients (39%). Concordance between the two methods was
observed in 36 strains. The two discordant results
corresponded to two strains that had a cluster pattern with six
distinct bands by RFLP and nonclustered patterns with two and four
bands by DRE-PCR. Data obtained from these patients suggested that they
were not epidemiologically related.
The epidemiological information about the patients was reevaluated in
the light of the data obtained by the IS6110 RFLP and DRE-PCR methods. Clusters I and III corresponded to strains from patients who were institutionalized in the same building, and therefore
epidemiological associations could be confirmed. Cluster II (four
strains) included two strains with identical RFLP patterns (strains 7 and 20) and two with distinct but very similar patterns, differing in
the position of a single band (strains 3 and 8). DRE-PCR results showed
identical patterns in three strains (strains 3, 7, and 20), with a
single band missing in the fourth (strain 8). The four patients were
not epidemiologically related. The patient infected with strain 3 had
been treated for lung tuberculosis previously, in 1996. Data from
patients in clusters IV and V showed that they were not
epidemiologically related. Considering that the two strains in cluster
V were found to differ in only one band by RFLP analysis but had
completely different DRE-PCR patterns, we concluded that DRE-PCR may be
even more discriminating than IS6110 RFLP analysis for
epidemiologic assessment.
Several strain-typing studies in community settings have been performed
by the IS6110 RFLP method. In the canton of Berne, 45 of 163 patients (27.6%) showed clustered patternsthe largest group included
drug addicts, homeless persons, and alcoholics (7)and in
Austria, only 2 of 31 patients (6.4%) showed the same RFLP pattern
(24). In developing countries, community-based studies
showed a higher proportion of clusters, suggesting that recent
transmission of M. tuberculosis is more frequent. In
Guadeloupe, 17 of 51 patients (33.4%) showed clustered patterns
(15), and in Honduras, 21 of 84 patients (25%) were
infected with cluster pattern strains (11). The present
study in Havana found 17 of 38 patients (44.7%) infected with cluster
pattern strains by RFLP analysis and 15 of 38 patients (39.4%)
infected with cluster pattern strains by DRE-PCR. Active surveillance
for tuberculosis had been performed in the prison where two clusters
were found, including a large cluster comprising seven patients. The
fact that the cluster pattern strains were isolated from young
incarcerated patients suggests that these infections resulted from
recent transmissions.
The RFLP and DRE-PCR methods identified the same clusters of
tuberculosis patients who were clearly linked epidemiologically. While
it is possible that the RFLP method identifies more strains with
different patterns in a collection of M. tuberculosis
isolates, in this study it did not offer any advantage over the DRE-PCR method in assessing an epidemiological situation. The RFLP method requires expensive laboratory equipment and is time-consuming. The
amount of extracted DNA needed to perform the procedure requires that
the primary culture have abundant growth. The entire procedure may take
several days or even weeks to obtain the final results. In a recent
publication, Sola et al. compared the discriminatory powers of DRE-PCR,
spoligotyping, IS6110 RFLP analysis, and direct-repeat RFLP
analysis in assessing epidemiological relatedness (16). They
found that spoligotyping plus DRE-PCR could give the same information
as could be obtained by IS6110 RFLP analysis. Spoligotyping requires less DNA and is less time-consuming than the RFLP
method, but a specially prepared membrane has to be provided. The
DRE-PCR method is clearly simpler, less expensive, and faster
than RFLP analysis and spoligotyping. The modification of the DRE-PCR
protocol introduced here resulted in the amplification of more bands
and therefore improved the discriminatory power of this technique. This
study showed that this modified strain-typing method, when used alone,
alone is accessible and produces the same epidemiological information
as does the RFLP method. This could be very useful in settings where
the latter method cannot be used routinely.
| |
ACKNOWLEDGMENTS |
We acknowledge Marcelo Palma Sircili for technical assistance and
Lucilaine Ferrazoli for assistance with the GelCompare software. We
thank Lee Riley for fruitful discussions.
Ernesto Montoro was the recipient of a 4-month BIOLAC-UNU fellowship
training grant. José Valdivia and Sylvia Cardoso Leão are
members of the RELACTB (Red de Latinoamérica y del Caribe de
Tuberculosisis).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Departamento de
Microbiologia, Imunologia, e Parasitologia, Universidade Federal de São Paulo, Rua Botucatu, 862 3° andar, São Paulo, Brazil.
Phone: (55-11) 5084-3213. Fax: (55-11) 571-6504. E-mail:
scleao.dmip{at}epm.br.
| |
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Journal of Clinical Microbiology, October 1998, p. 3099-3102, Vol. 36, No. 10
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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