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Journal of Clinical Microbiology, February 1999, p. 409-412, Vol. 37, No. 2
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Stability of Mycobacterium tuberculosis
IS6110 Restriction Fragment Length Polymorphism Patterns
and Spoligotypes Determined by Analyzing Serial Isolates from Patients
with Drug-Resistant Tuberculosis
Stefan
Niemann,*
Elvira
Richter, and
Sabine
Rüsch-Gerdes
Forschungszentrum Borstel, National Reference
Center for Mycobacteria, D-23845 Borstel, Germany
Received 5 October 1998/Returned for modification 27 October
1998/Accepted 16 November 1998
 |
ABSTRACT |
The stability of Mycobacterium tuberculosis
IS6110 fingerprint patterns and spoligotypes has been
assessed by analyzing serial isolates from patients with drug-resistant
tuberculosis. Altogether, 165 M. tuberculosis isolates
obtained from 56 patients have been analyzed. The time spans between
the first and the last or a changed isolate from one patient ranged
from 1 to 772 days. Among the 56 patients, 5 (9%) were infected with
isolates with changes in their IS6110 fingerprint patterns.
According to the total number of strains analyzed, 5% of the
subsequent isolates showed variations in their IS6110
restriction fragment length polymorphism patterns compared to the
pattern of the first isolates. Up to 10 isolates from one patient
sampled at time intervals of up to 772 days with no changes in their
IS6110 patterns have been analyzed. A statistically significant correlation could be found between changes in insertion sequence (IS) patterns and the increased time intervals over which the
isolates were obtained, whereas changes in IS patterns are not
correlated to changes in the drug resistance of the isolates. In
contrast to the observed variations in IS6110 fingerprint
patterns, no changes in the spoligotypes of the isolates analyzed could be found. In conclusion, our results confirm that the
IS6110 fingerprint patterns of M. tuberculosis
isolates have high degrees of stability. Compared to
IS6110, the direct repeat (DR) region, which is the basis
for spoligotyping, has a lower rate of change. Partial deletions, e.g.,
deletions induced by homologous recombination between the repetitive DR
elements, could not be detected in this study.
| |
INTRODUCTION |
IS6110 DNA fingerprinting
has become the standard method for analysis of the epidemiology of
tuberculosis (TB) on a molecular level (1, 2, 14, 15).
IS6110, a transposable sequence belonging to the
IS3 family (7), is found with few exceptions in
all members of the Mycobacterium tuberculosis complex and is apparently restricted to this group of organisms (2, 11). The epidemiological analysis of TB by IS6110 DNA
fingerprinting is based on the observation that the polymorphism of the
IS6110 restriction fragment length polymorphism (RFLP)
patterns among unrelated clinical isolates is very high, whereas
epidemiologically related M. tuberculosis strains show
identical or similar (one band variation) fingerprint patterns
(15). Hence, M. tuberculosis strains with
identical fingerprint patterns represent strains that have possibly
been recently transmitted, and these strains are likely to be members
involved in a chain of transmission.
For the correct interpretation of IS6110 fingerprinting
data, e.g., for determination of the percentage of reactivation versus the percentage of active transmission in a given population, it is
mandatory that the stability of the genetic marker used for the
analysis is known. Recently, the stability of IS6110
fingerprint patterns has been elucidated by analyzing serial isolates
of 49 patients in the United States (16). In this study, a
change in IS6110 banding pattern occurred in isolates from
12 of 49 patients (25%), indicating a relatively high degree of
instability of IS6110. However, a comparable high degree of
instability has not been observed in several other previously published
studies, each comprising smaller numbers of M. tuberculosis
strains (3, 9, 10, 14).
A new method for the characterization of M. tuberculosis
complex isolates, spoligotyping, can be used for the diagnosis of M. tuberculosis infections and epidemiological studies and
has recently been described by Kamerbeek et al. (6). It is
based on the detection of various nonrepetitive spacer sequences
located between small repetitive units (direct repeats [DRs]) in the
DR locus of M. tuberculosis complex strains (6).
Since the spoligotyping method is based on PCR, it is rapid and results
can be obtained directly from an M. tuberculosis culture
within 1 day. However, the discriminative power of spoligotyping
compared to that of IS6110 fingerprinting is less (4,
6), and consequently, its use for epidemiological studies of
M. tuberculosis is limited. Hence, a two-step strategy,
initial spoligotyping analysis followed by subtyping of strains
clustered by IS6110 fingerprinting to confirm the strains'
relationship, has been proposed (4). This strategy may allow
fast and efficient analysis on large numbers of isolates
(4). To apply this strategy, it is necessary to have
information about the "molecular clock" of the DR region and the
relative stability of spoligotypes compared to that of IS6110 fingerprint patterns. For example, one recombination
event may result in the deletion of a large part of the DR region. As a
consequence, the spoligotype of this strain will change dramatically, so that closely related strains may not be grouped together in the
initial analysis and possible cases of transmission may be overlooked.
So far, no data concerning the stability within the DR locus are
available, and it is not yet clear in which way and how often changes
in spoligotypes occur.
In this study we genotyped 165 isolates from 56 patients with
drug-resistant TB to elucidate the stabilities of M. tuberculosis IS6110 fingerprint patterns and
spoligotypes. Furthermore, from the data obtained in this study, the
relative stability of spoligotypes compared to that of
IS6110 fingerprint patterns and the feasibility of a
two-step procedure that uses both methods should be clarified.
| |
MATERIALS AND METHODS |
Bacterial strains.
One hundred sixty-five M. tuberculosis isolates received by the National Reference Center
for Mycobacteria between 1995 and 1997 were investigated by DNA
fingerprinting and spoligotyping. The isolates were obtained from 56 patients living in Germany. Drug susceptibility testing of all isolates
was done by the proportion method on Löwenstein-Jensen medium
and/or the modified proportion method with BACTEC 460TB (Becton
Dickinson Microbiology Systems, Cockeysville, Md.).
DNA genotyping techniques.
Extraction of DNA from
mycobacterial strains and DNA fingerprinting with IS6110 as
a probe were performed by standardized protocols (8, 12).
The IS6110 fingerprint patterns of mycobacterial strains
were analyzed with the GelCompar software (Windows 95, version 4.0;
Applied Maths, Kortrijk, Belgium) as described previously (8,
12).
Spoligotyping of isolates was performed as described by Kamerbeek et
al. (6). The spoligotyping analyses of serial isolates from
one patient were done side by side to allow an accurate comparison of
the spoligotypes.
Statistical analysis.
The chi-square test was performed to
determine whether changes in IS6110 RFLP patterns were
related to changes in drug resistance patterns or increased time
intervals between the retrieval of isolates.
| |
RESULTS |
In this study 165 serial isolates from 56 patients were analyzed
by the IS6110 DNA fingerprinting and spoligotyping methods. The isolates were selected from among approximately 600 drug-resistant M. tuberculosis isolates sent to the National Reference
Center for Mycobacteria between 1995 and 1997. All available isolates from one patient up to the first isolate with a change in
IS6110 fingerprint pattern have been analyzed. If no change
in the IS6110 pattern occurred, the last isolate analyzed
represents the last isolate from the patient that has so far been sent
to the National Reference Center for Mycobacteria. Twenty-three
additional isolates from 10 patients were excluded from this study
because the dates of primary isolation were not known exactly. However,
no changes in the IS6110 fingerprint patterns of these
isolate have been observed.
The time spans between the first and last or a changed isolate from one
patient ranged from 1 to 772 days (Table
1; Fig. 1A). The number of IS6110
copies per isolate varied from 3 to 17, with a mean of 10 (Table 1,
Fig. 1B). The drug resistance patterns of the isolates ranged from
monodrug resistance, e.g., resistance to isoniazid, to multidrug
resistance, e.g., resistance to isoniazid, ethambutol, rifampin, and
pyrazinamide (data not shown).
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|
TABLE 1.
Results of drug susceptibility tests, IS6110
DNA fingerprinting, and spoligotyping of serial isolates from
56 patients
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FIG. 1.
Time spans between the first and the last or a changed
isolate from the patients whose isolates were analyzed (A) and numbers
of IS6110 fingerprint bands (B). Changes in
IS6110 fingerprint patterns are shown as functions of the
time interval between the times of retrieval of isolates (A) and
numbers of fingerprint bands (B). IS, insertion sequence.
|
|
Among the 56 patients, 5 (9%) were infected with strains with changes
in their IS6110 fingerprint patterns between the first and
the last isolates that were obtained. All of these changes are based on
differences in one band in the fingerprint patterns compared to the
patterns for the first isolates (for four patients, one additional
band; for one patient, one less band [Table 1]). In terms of the
number of isolates analyzed, the proportion of IS6110
changes is 5% (if the numbers of first isolates from the patients were
subtracted from the total number of isolates tested). Changes in
IS6110 RFLP patterns have been observed over time intervals of from approximately 200 to 700 days in which the isolates were taken
(Table 1; Fig. 1A). No changes could be observed for time intervals of
less than approximately 190 days (Table 1). A significant correlation
was found between changes in IS6110 patterns and increased time intervals between the time of retrieval of isolates (P < 0.05). Changes were found in isolates with an intermediate
number (7 to 9) as well as with a large number (15 to 17) of bands
(Fig. 1B). All changes occurred in isolates obtained from men. However, only 20% of the patients included in this study were women, and for
half of them time intervals between the times of retrieval of the
isolates were less than 200 days, which are likely to be too short for
changes in IS6110 fingerprint patterns to occur (Table 1).
For isolates from nine patients, changes in the drug resistance
patterns (resistance to up to two additional antituberculous drugs) of
the isolates could be observed (Table 1). Although the serial isolates
from two patients showed changes in their IS6110
fingerprints as well as in their drug resistance patterns, in total no
significant correlation between these two events could be found.
The spoligotypes of the isolates analyzed had 9 to 39 hybridization
signals (Table 1) and differed markedly among the isolates. In contrast
to the observed changes in IS6110 fingerprint patterns, we
found no variation in spoligotypes (Table 1). In addition, we saw no
changes in the spoligotypes of the serial isolates from the 10 patients
excluded from this study.
| |
DISCUSSION |
In this study, the stabilities of the M. tuberculosis
IS6110 fingerprint patterns and spoligotypes have been
analyzed. Compared to the study of Yeh et al. (16), we found
a considerably higher degree of stability of IS6110 RFLP
patterns (if changes were related to the total number of isolates
analyzed). One possible reason for the higher degree of instability
observed in the study of Yeh and coworkers (16) may be that
only isolates whose times of retrieval were separated by at least 90 days have been analyzed. Nevertheless, limiting the number of patients
in our study to this group of patients, the percentage of
IS6110 changes remained less than that observed by Yeh et
al. (16) (14% according to the number of patients and 6%
according to the total number of isolates analyzed in the present study
but 25% according to the total number of isolates analyzed in the
study of Yeh et al. [16]). In any case, a study design
that excluded patients whose isolates were retrieved over intervals of
less than 90 days probably results in an overestimation of the real
rate of change in IS6110 RFLP patterns, because isolates
from patients in such studies are likely to have a higher rate of
IS6110 fingerprint changes. In our study, only
drug-resistant isolates have been analyzed, whereas Yeh et al.
(16) tested drug-susceptible as well as drug-resistant
strains. However, our results are in accordance with previously
published studies that analyzed comparatively small numbers of
regularly drug-susceptible isolates from patients repeatedly bearing
positive cultures, and all of those studies found a high degree of
stability of IS6110 patterns (3, 9, 10, 14).
Hence, the rate of change of IS6110 fingerprint patterns in
drug-resistant isolates seems not to differ from that in
drug-susceptible isolates. Consequently, the high rate of
IS6110 fingerprint changes found by Yeh et al. (16) may be a specific feature of the M. tuberculosis situation in San Francisco, Calif.
Our results confirm the high degree of stability of IS6110
RFLP patterns for M. tuberculosis bacteria that remain in
the bodies of patients. Up to 10 isolates obtained from one patient at
times separated by up to 772 days have been analyzed, and no change in
the IS6110 RFLP patterns of the isolate were found. However, in contrast to Yeh et al. (16), we found a significant
correlation between retrieval of isolates at increased time intervals
and changes in IS6110 RFLP patterns. In conclusion, our
results indicate that M. tuberculosis IS6110
patterns change at a relatively slow rate. In combination with the high
degree of variability of IS6110 fingerprint patterns found
for isolates from Germany (8) and other countries (5,
10, 13), our data stretch the hypothesis that patients whose
M. tuberculosis isolates have identical IS6110 fingerprint patterns are likely to be part of a recent chain of transmission. On the basis of our data, clustering rates should further
be based on identical fingerprint patterns, if other epidemiological data are not available.
In contrast to the observed changes in IS6110 fingerprint
patterns, we found no changes in the spoligotypes of the isolates tested. Hence, the DR region seems to have a lower rate of change than
IS6110. This fact is in accordance with the observed lower discriminative power of spoligotyping compared with that of
IS6110 fingerprinting (4, 6). Partial deletions,
e.g., via homologous recombination, do not seem to be frequent in the
DR region. Hence, a two-step procedure for epidemiological studies of
M. tuberculosis based on an initial typing of all isolates
by spoligotyping, followed by subtyping of clustered isolates by
IS6110 fingerprinting, as proposed by Gouguet de la
Salmonière et al. (4), seems to be feasible. Since the
initial spoligotyping analysis is fast and does not need a well-grown
bacterial culture, this procedure should simplify and speed up
epidemiological studies comprising large numbers of strains. Moreover,
our results clearly demonstrate that isolates with different
spoligotypes are most likely not related.
| |
ACKNOWLEDGMENTS |
We thank Andreas Zyzik, Borstel, Germany, for excellent technical
assistance and, furthermore, Kristin Kremer, Dick van Soolingen, and
Jan van Embden, Bilthoven, The Netherlands, for technical support.
Parts of this work were supported by the Robert Koch-Institut, Berlin, Germany.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
Forschungszentrum Borstel, National Reference Center for Mycobacteria,
Parkallee 18, D-23845 Borstel, Germany. Phone: (49)-4537-188658. Fax:
(49)-4537-188311. E-mail: sniemann{at}fz-borstel.de.
| |
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Journal of Clinical Microbiology, February 1999, p. 409-412, Vol. 37, No. 2
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
