Prevalence of Mycobacterium tuberculosis in Taiwan: A Model for Strain Evolution Linked to Population Migration

The global evolution and spread of Mycobacterium tuberculosis (MTB), one of the most successful bacterial pathogens, remain a mystery. Advances in molecular technology in the past decade now make it possible to understand MTB strain evolution and transmission in the context of human population migration. Taiwan is a relatively isolated island, serving as a mixing vessel over the past four centuries as colonization by different waves of ethnic groups occurred. By using mycobacterial tandem repeat sequences as genetic markers, the prevalence of MTB strains in Taiwan revealed an interesting association with historical migrations of different ethnic populations, thus providing a good model to explore the global evolution and spread of MTB

Molecular typing of Mycobacterium tuberculosis isolated from adult patients with tubercular spondylitis

Background/PurposeTuberculosis (TB) is endemic in Taiwan and usually affects the lung, spinal TB accounting for 1–3% of all TB infections. The manifestations of spinal TB are different from those of pulmonary TB. The purpose of this study was to define the epidemiological molecular types of mycobacterial strains causing spinal TB.MethodsWe retrospectively reviewed the medical charts of adult patients diagnosed with spinal TB from January 1998 to December 2007. Patients with positive culture results and/or pathological findings characteristic of TB were enrolled in this study. Spoligotyping was performed to type the Mycobacterium tuberculosis isolates.ResultsA total of 38 patients with spinal TB were identified. Their mean age was 68 years, and their median duration of symptoms was 60 days (range 3–720 days). The lumbar and thoracic spine accounted for 76% of the sites involved. Thirteen specimens (from seven male and six female patients) were available for typing. Spoligotyping of these 13 specimens revealed three Beijing (23%) and 10 non-Beijing types (77%). The non-Beijing types included two EAI2 Manilla (15%), two H3 (15%), two unclassified (15%), and one each of BOVIS1, U, T2, and orphan type. No significant predominant strain was found in this study, and no drug-resistant Beijing strains were identified.ConclusionTB spondylitis was found to occur in older patients. Spoligotyping results showed that most of the TB spondylitis cases were caused by non-Beijing type Mycobacterium tuberculosis

Pathological granuloma fibrosis induced by agar-embedded Mycobacterium abscessus in C57BL/6JNarl mice

IntroductionPulmonary granuloma diseases caused by Mycobacterium abscessus (M. abscessus) have increased in past decades, and drug-resistance in this pathogen is a growing public health concern. Therefore, an animal model of chronic granuloma disease is urgently needed.MethodsIn this study, M. abscessus embedded within agar beads (agar-AB) was used to develop such a model in C57BL/6JNarl mice.ResultsChronic infection was sustained for at least 3 months after agar-AB infection, visible granulomas spread in the lungs, and giant cells and foamy cells appeared in the granulomas. More importantly, pulmonary fibrosis progressed for 3 months, and collagen fibers were detected by Masson trichrome staining. Further, inducible nitric oxide synthase (iNOS) was highly expressed within the alveolar space, and the fibrosis-mediator transforming growth factor beta (TGF-β) began to be expressed at 1 month. Hypoxia-inducible factor (HIF-1α) expression also increased, which aided in normalizing oxygen partial pressure.DiscussionAlthough the transient fibrosis persisted for only 3 months, and the pulmonary structure resolved when the pathogen was cleard, this pulmonary fibrosis model for M. abscessus infection will provide a novel test platform for development of new drugs, regimens, and therapies

Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania

In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam

Molecular epidemiology and evolutionary genetics of Mycobacterium tuberculosis in Taipei

<p>Abstract</p> <p>Background</p> <p>The control of tuberculosis in densely populated cities is complicated by close human-to-human contacts and potential transmission of pathogens from multiple sources. We conducted a molecular epidemiologic analysis of 356 <it>Mycobacterium tuberculosis </it>(MTB) isolates from patients presenting pulmonary tuberculosis in metropolitan Taipei. Classical antibiogram studies and genetic characterization, using mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing and spoligotyping, were applied after culture.</p> <p>Methods</p> <p>A total of 356 isolates were genotyped by standard spoligotyping and the strains were compared with in the international spoligotyping database (SpolDB4). All isolates were also categorized using the 15 loci MIRU-VNTR typing method and combin with <it>NTF </it>locus and RD deletion analyses.</p> <p>Results</p> <p>Of 356 isolates spoligotyped, 290 (81.4%) displayed known spoligotypes and 66 were not identified in the database. Major spoligotypes found were Beijing lineages (52.5%), followed by Haarlem lineages (13.5%) and EAI plus EAI-like lineages (11%). When MIRU-VNTR was employed, 140 patterns were identified, including 36 clusters by 252 isolates and 104 unique patterns, and the largest cluster comprised 95 isolates from the Beijing family. The combination of spoligotyping and MIRU-VNTR revealed that 236 (67%) of the 356 isolates were clustered in 43 genotypes. Strains of the Beijing family was more likely to be of modern strain and a higher percentage of multiple drug resistance than other families combined (P = 0.08). Patients infected with Beijing strains were younger than those with other strains (mean 58.7 vs. 64.2, p = 0.02). Moreover, 85.3% of infected persons younger than 25 years had Beijing modern strain, suggesting a possible recent spread in the young population by this family of TB strain in Taipei.</p> <p>Conclusion</p> <p>Our data on MTB genotype in Taipei suggest that MTB infection has not been optimally controlled. Control efforts should be reinforced in view of the high prevalence of the Beijing strain in young population and association with drug resistance.</p

Prevalence of Mycobacterium tuberculosis strain genotypes in Taiwan reveals a close link to ethnic and population migration

Taiwan is a relatively isolated island, serving as a mixing vessel for colonization by different waves of ethnic and migratory groups over the past 4 centuries. The potential transmission pattern of Mycobacterium tuberculosis in different ethnic and migratory populations remains to be elucidated. By using mycobacterial tandem repeat sequences as genetic markers, the prevalence of M. tuberculosis strains in Taiwan revealed a close link to the historical migration. Interestingly, the M. tuberculosis strain in the aborigines of Eastern and Central Taiwan had a dominance of the Haarlem (Dutch) strain while those in Southern Taiwan had a dominance of the East-African Indian (EAI) strain. The prevalence of different M. tuberculosis strains in specific ethnic populations suggests that M. tuberculosis transmission is limited and restricted to close contact. The prevalence of the Beijing modern strain in the young population causes a concern for M. tuberculosis control, because of high virulence and drug resistance. Furthermore, our data using molecular genotyping should provide valuable information on the historical study of the origin and migration of aborigines in Taiwan

Effect of Type 2 Diabetes Mellitus on the Clinical Severity and Treatment Outcome in Patients With Pulmonary Tuberculosis: A Potential Role in the Emergence of Multidrug-resistance

Background/PurposeA globally increasing trend of type 2 diabetes mellitus (DM), the rising prevalence of tuberculosis (TB) in many countries, and the emergence of multidrug-resistant TB (MDR-TB) in recent years pose a serious challenge for TB control.MethodsWe investigated pulmonary tuberculosis patients with and without type 2 DM (DMTB and TB, respectively) treated at the Chest Hospital, Taiwan, between November 2004 and October 2005.ResultsOne hundred and ninety-two new patients (60 DMTB, 132 TB) were regularly treated for a full course (≥ 6 months) and prospectively followed for more than 1 year. The DMTB patients had more severe infections (far-advanced: 45.0% vs. 22.7%, p < 0.01), higher mycobacterial loads (sputum smear: 2.9 ± 1.3+ vs. 1.9 ± 1.7+, p < 0.01), higher treatment failure rates (17% vs. 2%, p < 0.01), and longer delayed clearance of mycobacteria than did the TB patients (2.5 ± 3.0 months vs. 1.6 ± 1.4 months, p < 0.01). After one year, three DMTB patients and one TB patient had MDR-TB (5.0% vs. 0.8%, p = 0.056). Bacterial genotyping revealed that the proportion of mycobacterial strains was not significantly different in DMTB and TB patients (Beijing strain: 46.7% vs. 40.6%, Non-Beijing strain: 53.3% vs. 59.4%, p = 0.632).ConclusionDMTB patients have more severe TB infections, which require longer treatment and are more likely to develop MDR-TB than are patients with TB alone

Genomics Study of Strains from Different Ethnic Populations in Taiwan

To better understand the transmission and evolution of Mycobacterium tuberculosis (MTB) in Taiwan, six different MTB isolates (representatives of the Beijing ancient sublineage, Beijing modern sublineage, Haarlem, East-African Indian, T1, and Latin-American Mediterranean (LAM)) were characterized and their genomes were sequenced. Discriminating among large sequence polymorphisms (LSPs) that occur once versus those that occur repeatedly in a genomic region may help to elucidate the biological roles of LSPs and to identify the useful phylogenetic relationships. In contrast to our previous LSP-based phylogeny, the sequencing data allowed us to determine actual genetic distances and to define precisely the phylogenetic relationships between the main lineages of the MTB complex. Comparative genomics analyses revealed more nonsynonymous substitutions than synonymous changes in the coding sequences. Furthermore, MTB isolate M7, a LAM-3 clinical strain isolated from a patient of Taiwanese aboriginal origin, is closely related to F11 (LAM), an epidemic tuberculosis strain isolated in the Western Cape of South Africa. The PE/PPE protein family showed a higher dn/ds ratio compared to that for all protein-coding genes. Finally, we found Haarlem-3 and LAM-3 isolates to be circulating in the aboriginal community in Taiwan, suggesting that they may have originated with post-Columbus Europeans. Taken together, our results revealed an interesting association with historical migrations of different ethnic populations, thus providing a good model to explore the global evolution and spread of MTB

The Pattern of Cytokine Production <i>In Vitro</i> Induced by Ancient and Modern Beijing <i>Mycobacterium tuberculosis</i> Strains

<div><p>It is unclear to what extent the host-responses elicited by Beijing versus non-Beijing strains of <i>Mycobacterium tuberculosis</i> (MTB) contribute to the predominance of modern Beijing strains in Taiwan and some other Asian countries. The purpose of this study was to compare the expression profiles of virulence-related genes in human monocyte-derived macrophages infected in vitro with Beijing (ancient and modern strains) and non-Beijing strains (EAI strains) of MTB that are epidemic in Taiwan. We found that modern Beijing strains induced lower levels of pro-inflammatory cytokines, whereas EAI strains induced higher levels. Notably, the most prevalent modern Beijing sub-lineage, possessing intact RD150 and RD142 chromosomal regions, induced very low levels of pro-inflammatory cytokines, especially interleukin-1β. Moreover, in an intracellular growth assay, the survival of the same modern Beijing strain in human monocyte-derived macrophages was significantly higher than that of an ancient Beijing strain and an EAI strain. Taken together, these results may explain why modern Beijing strains of MTB predominate in Taiwan.</p></div