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Journal of Clinical Microbiology, April 1998, p. 1003-1007, Vol. 36, No. 4
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Diversity of DNA Fingerprints of
Mycobacterium tuberculosis Isolates in the United
States
Zhenhua
Yang,1,2
Peter F.
Barnes,3
Fernando
Chaves,1,2,4
Kathleen
D.
Eisenach,1,2,5
Stephen E.
Weis,6
Joseph H.
Bates,1,5,7 and
M. Donald
Cave1,8,*
Regional Tuberculosis Genotyping
Laboratory1 and Departments of
Pathology,2
Microbiology-Immunology,4
Medicine,7 and
Anatomy,8 University of Arkansas
for Medical Sciences and John L. McClellan Memorial Veterans
Hospital, Little Rock, Arkansas;
Center for Pulmonary and Infectious
Disease Control, University of Texas Health Center at Tyler,
Tyler,3 and
University of North Texas
Health Center at Fort Worth, Fort
Worth,6 Texas; and
Department of
Clinical Microbiology and Infectious Diseases, Hospital
General Penitenciario, Madrid, Spain5
Received 31 October 1997/Returned for modification 10 December
1997/Accepted 20 December 1997
 |
ABSTRACT |
To investigate the diversity of IS6110 fingerprints of
Mycobacterium tuberculosis isolates in the United States
and to determine if matching IS6110 fingerprints represent
recent interstate tuberculosis transmission, we performed restriction
fragment length polymorphism analysis of M. tuberculosis
isolates from 1,326 patients in three geographically separated states.
Seven hundred ninety-five different IS6110 fingerprint
patterns were generated, and pattern diversity was similar in each
state. Ninety-six percent of the fingerprint patterns were observed in
only one state, demonstrating that most IS6110 fingerprint
patterns are confined to a single geographic location. Of the
IS6110 fingerprint patterns that were shared by isolates
from more than one state, most isolates with 1 to 5 IS6110
copies were separable by pTBN12 fingerprinting whereas those with >15
copies were not. One high-copy-number M. tuberculosis strain had identical IS6110 and pTBN12 fingerprints and
included 57 isolates from three states. Epidemiological data
demonstrated significant recent transmission of tuberculosis within
each city but not among the states. This suggests that identical
fingerprints of isolates from geographically separate locations most
likely reflect interstate tuberculosis transmission in the past, with subsequent intrastate spread of disease. Further evaluation of M. tuberculosis strains that cause outbreaks in different geographic locations will provide insight into the epidemiological and
bacteriological factors that facilitate the spread of tuberculosis.
| |
INTRODUCTION |
Our understanding of the dynamics of
tuberculosis transmission has been greatly enhanced by the development
of genotyping methods that allow identification of specific strains of
Mycobacterium tuberculosis. The most widely used genotyping
method is DNA fingerprinting based on restriction fragment length
polymorphism (RFLP) analysis with the insertion element
IS6110, which produces extensive fingerprint diversity among
M. tuberculosis isolates (6, 9, 12, 13, 16). In
some locations, epidemiological and RFLP analyses suggest that
identical IS6110 fingerprints among M. tuberculosis isolates are a marker of recent tuberculosis
transmission (1, 3, 11, 15), whereas in other areas,
identical IS6110 fingerprints do not indicate recent
tuberculosis transmission (4, 5). Because most
IS6110 fingerprint analyses of M. tuberculosis
isolates have been confined to specific geographic locales (1-5,
11, 15), the diversity of IS6110 fingerprints in
different parts of the United States has not been systematically
evaluated. In addition, it is uncertain if matching fingerprints
obtained from patients in different states indicate that the patients
are epidemiologically linked by recent tuberculosis transmission. To
examine these issues, we performed RFLP analysis of M. tuberculosis isolates obtained from 1,326 patients from three
geographically separated states.
| |
MATERIALS AND METHODS |
M. tuberculosis strains.
We studied one M. tuberculosis isolate from each of 1,326 patients in California,
Texas, and Colorado. One thousand one hundred seventy-six isolates
(89%) included all available isolates from public health departments
at five geographically separate locations during specific time periods.
These locations were in California (Alameda County and Contra Costa
County [308 isolates, 1992 to 1994] and central Los Angeles [214
isolates, 1993 to 1995]), Texas (Fort Worth [219 isolates, 1993 to
1995] and El Paso [177 isolates, 1994 to 1995]), and Colorado
(Denver, 256 isolates, 1989 to 1994). In addition, we included 150 drug-resistant isolates obtained throughout the state of Texas (1991 to
1995).
All isolates were identified as M. tuberculosis by the
submitting laboratories. The isolates were received on
Lowenstein-Jensen slants, and each was subcultured in 5 ml of
Dubos-Tween 80 medium supplemented with albumin (Difco, Detroit, Mich.)
and then incubated at 37°C for 2 to 3 weeks prior to DNA extraction.
DNA fingerprinting.
Chromosomal DNA was prepared by
chloroform-isoamyl alcohol extraction (14). One microgram of
DNA from each isolate was either restricted with PvuII and
then fingerprinted with the IS6110 probe or restricted with
AluI and then fingerprinted with the pTBN12 probe.
Fingerprinting was performed by standard methods (8, 17).
The DNA molecular size standard used for IS6110
fingerprinting was PvuII-restricted chromosomal DNA of
M. tuberculosis H37Rv and two additional DNA fragments which
hybridize to IS6110 (18). A 1-kb DNA ladder was
the DNA molecular size standard for pTBN12 fingerprinting. The DNA
probes were prepared as reported previously (18) and labeled
with [
-32P]dCTP by the random-primer method
(10).
Fingerprint analyses and comparison of patterns.
For
computer-assisted analyses of IS6110 fingerprints,
hybridized blots were exposed to a phosphor screen, the screen was scanned with Image Quant software (Molecular Dynamics, Sunnyvale, Calif.), and the patterns were analyzed with Whole Band Analyzer software (version 3.3; Bioimage, Ann Arbor, Mich.). A band size deviation of up to 2.5% was allowed when matching the patterns. Matching was determined by the average linkage clustering method. Patterns that matched at the 100% level were considered identical, and
isolates with identical patterns were considered a cluster.
The geographic source of each IS6110 fingerprint pattern was
recorded, and a fingerprint pattern file was developed for each state;
this file contained all patterns generated by the isolates from that
state. IS6110 fingerprints from different states were compared with each other, as well as with patterns found in a previous
study of 210 M. tuberculosis isolates obtained from inmates of the prison system of Madrid, Spain (7). pTBN12
fingerprints in adjacent lanes were visually compared.
| |
RESULTS |
IS6110 fingerprints in the study population.
The
IS6110 fingerprints for isolates from 1,326 patients were
grouped according to the number of copies of IS6110 (Fig.
1). Two isolates with no copies of
IS6110 were confirmed to be M. tuberculosis by a
DNA probe method (Accuprobe; Gen-Probe, San Diego, Calif.) and
conventional biochemical tests. Three hundred thirty-two (25%)
isolates contained 1 to 5 copies of IS6110 (low-copy-number strains), 782 isolates (59%) contained 6 to 15 copies, and 212 isolates (16%) had 16 or more copies (high-copy-number strains).
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FIG. 1.
Comparison of diversities of IS6110
fingerprints. The light bars show the frequency distribution of
IS6110 in M. tuberculosis isolates collected from
1,326 patients in three geographically separated states; the dark bars
represent the frequency distribution of 795 IS6110
fingerprint patterns observed in M. tuberculosis isolates
from the same patients, excluding two whose isolates were found to lack
IS6110.
|
|
The two isolates with no copies of IS
6110 were excluded, and
the remaining 1,324 isolates showed 795 different fingerprint
patterns,
confirming the extensive polymorphism of IS
6110 fingerprints
in the United States. Of the 795 patterns, 80 (10%) were
low-copy-number
strains, 588 (74%) contained 6 to 15 copies of
IS
6110, and 127
(16%) were high-copy-number strains. As
shown in Fig.
1, the diversity
of DNA fingerprint patterns was highest
in strains with 6 to 15
copies of IS
6110, intermediate in
high-copy-number strains, and
lowest in low-copy-number strains.
Diversity of IS6110 patterns within three states.
In Table 1, the diversities of
IS6110 fingerprint patterns in the three states are
compared. All three states showed similar percentages of clustered
isolates and similar degrees of pattern diversity, as estimated by the
mean number of isolates per pattern.
When DNA fingerprint patterns of the three states were compared, it was
found that 762 (96%) of the 795 patterns were restricted
to one state
and only 33 (4%) were not, demonstrating that most
IS
6110
patterns in this set are confined to a specific geographic
location.
Although the number of IS
6110 patterns found in two
or more
states was small, the number of isolates with these patterns
was large,
including 397 (30%) of the 1,326 isolates. Of these
397 isolates, 245 were low-copy-number strains comprising 12 fingerprint
patterns and 152 had 6 or more copies of IS
6110 comprising 21
fingerprint
patterns. The distribution of these 21 patterns in
the three states is
shown in Table
2.
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|
TABLE 2.
Isolates of M. tuberculosis obtained from more
than one state that shared fingerprint patterns having six or
more IS6110 copiesa
|
|
Evaluation of IS6110 patterns shared by isolates from
more than one state.
To determine if the M. tuberculosis isolates from different states with identical
IS6110 fingerprints represented the same genotype, we
studied isolates from 32 of the 33 interstate clusters. One isolate
from each state in the cluster was randomly selected, including 30 low-copy-number strains comprising 12 patterns and 46 isolates with 6 or more IS6110 copies comprising 20 patterns. The
IS6110 fingerprints of these 76 isolates were reexamined
after electrophoresis of restriction digests in adjacent lanes on the same gel. This analysis confirmed that the IS6110
fingerprints were identical in all cases (data not shown).
The 76 isolates were then subjected to secondary fingerprinting with
the pTBN12 probe. This probe was used because it distinguishes
M. tuberculosis strains with identical low-copy-number
IS
6110 fingerprints (
5,
8,
18) and because
pTBN12-based fingerprinting
results have been validated by
epidemiological studies (
3,
5,
18). The percentage of
isolates that were differentiated
by pTBN12 fingerprinting varied
inversely with the number of IS
6110 copies. Twenty-four
(80%) of 30 low-copy-number strains were no
longer clustered after
pTBN12 typing, compared to none of 6 high-copy-number
strains (Table
3). This finding is consistent with the
intuitive
concept that the random probability of two isolates having
identical
IS
6110 fingerprints increases as the number of
IS
6110 copies falls.
The identical IS
6110 and pTBN12 patterns observed for some
M. tuberculosis isolates obtained from different states
could have
arisen by chance alone, or they could represent interstate
transmission
of tuberculosis. To evaluate these possibilities, we
compared
the 795 fingerprint patterns of the 1,326 isolates from the
United
States with 79 fingerprint patterns previously found for 210 isolates
from prisoners in Madrid, Spain (
7). This
population was selected
because these two groups of patients were
extremely unlikely to
be epidemiologically linked. Only one pattern
with three IS
6110 copies was shared by one Spanish isolate
and four Texas isolates.
pTBN12 patterns were identical for the Texas
isolates and different
from the Spanish isolate. These findings suggest
that identical
IS
6110 and pTBN12 fingerprints in different
geographic locations
are unlikely to arise by chance alone. Therefore,
the isolates
with identical fingerprint patterns common to two or more
states
may well have resulted from interstate transmission of
tuberculosis.
Evaluation of the largest interstate cluster.
To determine if
interstate transmission of tuberculosis in the recent past accounted
for clustering of isolates from different states, we performed a more
detailed fingerprinting and epidemiological analysis of the largest
interstate cluster, which included 57 isolates with 21 copies of
IS6110 (cluster 21-1 in Table 2). Thirty-nine patients were
from California (38 from Los Angeles and 1 from Alameda-Contra Costa
County), 16 patients were from Fort Worth, Tex., and two patients were
from Denver, Colo. Twenty-six of these isolates were randomly selected
for pTBN12 secondary fingerprinting (one isolate from
Alameda-Contra Costa County, Calif.; 19 isolates from Los Angeles,
Calif.; one isolate from Denver, Colo.; and 5 isolates from Fort Worth,
Tex.), and all fingerprints were identical, suggesting that these
isolates represent the same genotype. Examples of these
IS6110 and pTBN12 fingerprints are shown in Fig.
2.
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FIG. 2.
IS6110 (left panel) and pTBN12 (right panel)
fingerprint patterns of four M. tuberculosis isolates from
the largest cluster found in more than one state. The isolates were
obtained from Denver, Colo. (lane 1), Alameda-Contra Costa County,
Calif. (lane 2), Los Angeles, Calif. (lane 3), and Fort Worth, Tex.
(lane 4).
|
|
Epidemiological information regarding the patients in Los Angeles and
Fort Worth, who comprised 95% (54 of 57) of the largest
cluster, was
obtained. Of the 38 patients from central Los Angeles,
37 were homeless
or marginally housed, often eating and spending
time at homeless
shelters. Of the 34 patients who were interviewed,
28 spent long
periods at one of three homeless shelters, suggesting
that these were
sites of disease transmission. None of the patients
had lived in or
near Fort Worth. Three patients were born in Texas
and had moved to Los
Angeles 5, 36, and 50 years prior to development
of tuberculosis.
Of the 16 patients from Fort Worth, five were homeless or marginally
housed persons who lived in the same area. Four patients
lived in a
small African-American community within Fort Worth.
These two groups
were epidemiologically linked by drug users who
were members of both
communities. The other seven patients were
from different economic and
ethnic groups and were not epidemiologically
linked. Two of the 16 patients had lived in Los Angeles. One patient
lived 10 miles from
central Los Angeles for 4 months in 1990,
3 years prior to being
diagnosed with tuberculosis. Her spouse
was a drug user who often
brought others to visit the residence.
The second patient was homeless
in central Los Angeles at various
periods from 1983 to 1990 and
developed tuberculosis in 1993.
None of the patients from Fort Worth or
Los Angeles was listed
in the tuberculosis registry of the other city
or had traveled
to the other city within 3 years of diagnosis.
| |
DISCUSSION |
Our findings confirm and extend previous observations regarding
the extensive diversity of IS6110 fingerprints among
M. tuberculosis isolates in the United States. For isolates
from 1,324 patients from three states, 795 IS6110
fingerprint patterns were generated, and similar degrees of pattern
diversity were observed in each state. Ninety-six percent of the
fingerprint patterns were found in only one state, demonstrating that
most IS6110 patterns are confined to a specific geographic
location. Of the IS6110 fingerprint patterns that were
shared by more than one state, most low-copy-number patterns were
separable by pTBN12 fingerprinting whereas high-copy-number patterns
were not. In one large cluster, epidemiological data demonstrated
extensive intrastate transmission of tuberculosis and suggested the
potential for interstate disease transmission. Since none of the
patients in Fort Worth or Los Angeles had traveled to the other city
within 3 years of the diagnosis of tuberculosis, a more plausible
hypothesis is that transmission of this strain between these areas
occurred a few years ago, with subsequent local transmission of the
disease. No evidence of recent interstate transmission was found,
demonstrating that matching IS6110 and pTBN12 fingerprints
of isolates from geographically separate locations are not indicative
of a recent tuberculosis outbreak.
pTBN12 fingerprinting distinguishes M. tuberculosis isolates
with identical IS6110 fingerprints comprised of five or
fewer fragments, and pTBN12 fingerprinting results correlate well with epidemiological data suggestive of tuberculosis transmission
(18). In previous studies, M. tuberculosis
isolates from the same locale with identical fingerprints containing
six or more copies of IS6110 were not further discriminated
by pTBN12 fingerprinting (5, 8). In contrast, we found that
the percentage of isolates that were differentiated by pTBN12
fingerprinting varied inversely with the number of IS6110
copies (Table 3). More than one-third of our isolates with identical
fingerprints containing 6 to 10 copies of IS6110 were
separated by pTBN12 fingerprinting. Therefore, in evaluating patients
from different geographic regions, M. tuberculosis isolates
should be considered part of a cluster only when the isolates have
matching IS6110 and pTBN12 fingerprints. pTBN12 fingerprinting is less essential for confirmation of clustering among
isolates with six or more IS6110 copies in the same
geographic location, because the probability of disease transmission is
higher.
Our findings provide strong evidence that a single M. tuberculosis strain caused disease in a substantial number of
patients in more than one state. The isolates from different states
were high-copy-number strains with identical IS6110 and
pTBN12 fingerprints, and epidemiological data confirmed significant
transmission of this strain within the cities of Fort Worth, Tex., and
Los Angeles, Calif. Epidemiological investigations did not reveal
recent contact between tuberculosis patients in these cities,
indicating that identical fingerprint patterns of M. tuberculosis isolates from different locations do not necessarily
indicate recent disease transmission between these locations. It is
more likely that our findings reflect interstate transmission of
tuberculosis a few years ago with subsequent intrastate spread of
disease, and our epidemiological data suggested the potential for such
linkages. Population groups at increased risk for tuberculosis, such as homeless persons and drug users, are highly mobile, favoring continued spread of M. tuberculosis across state borders.
Identification of M. tuberculosis strains that cause
outbreaks in different geographic locations is important for at least two reasons. First, it improves our understanding of the
epidemiological factors that facilitate the spread of tuberculosis.
Second, it may allow identification of biological characteristics of
M. tuberculosis strains that favor disease transmission. An
understanding of these factors will enhance our understanding of the
pathogenesis of tuberculosis and permit development of more-effective
tuberculosis control strategies.
| |
ACKNOWLEDGMENTS |
This study was supported by a CDC-VA interagency agreement for
the Tuberculosis Genotyping and Surveillance Network and by the
National Institutes of Health (grants 1R01A135265 and AI35222). Peter
F. Barnes holds the Margaret E. Byers Cain Chair for Tuberculosis Research.
We thank Don Cunningham, Stephen Kincaid, and Susan Rowland for
excellent technical assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: VA Hospital,
Room GB-126, 4300 W. 7th St., Little Rock, AR 72205. Phone: (501)
661-1202, ext. 2981. Fax: (501) 664-6748. E-mail:
mdcave{at}life.uams.edu.
| |
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Journal of Clinical Microbiology, April 1998, p. 1003-1007, Vol. 36, No. 4
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
