Genetic variability and consequence of Mycobacterium tuberculosis lineage 3 in Kampala-Uganda

Authors: Eddie M. Wampande aff001;  Peter Naniima aff001;  Ezekiel Mupere aff003;  David P. Kateete aff001;  LaShaunda L. Malone aff004;  Catherine M. Stein aff005;  Harriet Mayanja-Kizza aff004;  Sebastien Gagneux aff007;  W. Henry Boom aff005;  Moses L. Joloba aff001
Authors place of work: Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda aff001;  Department of Veterinary Medicine, Clinical and Comparative medicine, College of Veterinary Medicine, Animal Resources and Bio Security, Makerere University, Kampala, Uganda aff002;  Department of Pediatrics and Child Health College of Health Sciences, Makerere University, Kampala, Uganda aff003;  Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda aff004;  Tuberculosis Research Unit, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, Uinted States of America aff005;  Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, Uinted States of America aff006;  Swiss Tropical and Public Health Institute, Basel, Switzerland aff007;  University of Basel, Basel, Switzerland aff008
Published in the journal: PLoS ONE 14(9)
Category: Research Article
doi: 10.1371/journal.pone.0221644



Limited data existed exclusively describing Mycobacterium tuberculosis lineage 3 (MTB-L3), sub-lineages, and clinical manifestations in Kampala, Uganda. This study sought to elucidate the circulating MTB-L3 sub-lineages and their corresponding clinical phenotypes.


A total of 141 M. tuberculosis isolates were identified as M. tuberculosis lineage 3 using Single nucleotide polymorphism (SNP) marker analysis method. To ascertain the sub-lineages/sub-strains within the M. tuberculosis lineage 3, the direct repeat (DR) loci for all the isolates was examined for sub-lineage specific signatures as described in the SITVIT2 database. The infecting sub-strains were matched with patients’ clinical and demographic characteristics to identify any possible association.


The data showed 3 sub-lineages circulating with CAS 1 Delhi accounting for 55% (77/141), followed by CAS 1-Kili 16% (22/141) and CAS 2/CAS 8% (12/141). Remaining isolates 21% (30/141) were unclassifiable. To explore whether the sub-lineages differ in their ability to cause increased severe disease, we used extent of lung involvement as a proxy for severe disease. Multivariable analysis showed no association between M. tuberculosis lineage 3 sub-lineages with severe disease. The risk factors associated with severe disease include having a positive smear (OR = 9.384; CI 95% = 2.603–33.835), HIV (OR = 0.316; CI 95% = 0.114–0.876), lymphadenitis (OR = 0. 171; CI 95% = 0.034–0.856) and a BCG scar (OR = 0.295; CI 95% = 0.102–0.854).


In Kampala, Uganda, there are three sub-lineages of M. tuberculosis lineage 3 that cause disease of comparable severity with CAS-Dehli as the most prevalent. Having HIV, lymphadenitis, a BCG scar and a smear negative status is associated with reduced severe disease.


Biology and life sciences – Organisms – People and places – Geographical locations – Anatomy – Medicine and health sciences – Microbiology – Medical microbiology – Microbial pathogens – Bacteria – Pathology and laboratory medicine – Pathogens – Physiology – Diagnostic medicine – Signs and symptoms – Africa – Infectious diseases – Bacterial diseases – Tuberculosis – Tropical diseases – Viral pathogens – Immunodeficiency viruses – HIV – Retroviruses – Lentivirus – Viruses – RNA viruses – Actinobacteria – Mycobacterium tuberculosis – Body fluids – Blood – Physiological processes – Extensively drug-resistant tuberculosis – Epidemiology – Medical risk factors – Coughing – Uganda


Seven major lineages of human-adapted Mycobacterium tuberculosis complex (MTBC) are preferentially distributed in specific geographical niches, where they are the primary cause of Tuberculosis (TB). Geographic dispersion includes Mycobacterium tuberculosis (M. tuberculosis) lineage 1 (Indo Oceanic) found in areas along the Indian ocean, M. tuberculosis lineage 2 found majorly in east Asia, M. tuberculosis lineage 3 found in East Africa and India, M. tuberculosis lineage 4 (Euro-American) found mainly in Africa, Europe and America, M. tuberculosis lineage 5 & 6 (M. africanum1 & 2) found exclusively in West Africa and M. tuberculosis lineage 7 found primarily in Ethiopia [13]. The M. tuberculosis lineage 3 (MTB-L3), also known as the Central Asian strains (CAS), occurs predominantly in areas around the Indian Ocean, East Africa and India [4, 5]. The genetic diversity of the CAS can be defined based on specific single nucleotide polymorphisms (SNPs) [6, 7], genomic deletion, also known as long sequence polymorphism (LSP) [4, 5], and a particular spoligotype pattern [8]. The latter can further subdivide the main M. tuberculosis lineage 3 into specific sub-lineages [8]. Emergence and spread of M. tuberculosis lineages to other niches (where they were originally absent) has been associated with immigration, clinical and demographic factors, as well as evolution of MTB strains [9, 10]. Understanding mechanisms shaping transmission of MTB strains can provide a lead about the potential approaches for TB control.

The data from our previous studies showed that in Kampala, Uganda, there are 3 main M. tuberculosis lineages circulating, of these 11% were M. tuberculosis lineage 3 [11]. Moreover, findings also revealed that all the M. tuberculosis predominant in Kampala were equally virulent (based on cavitation as a proxy for virulence). Nevertheless, elsewhere authors have reported that different M. tuberculosis complex lineages infections present with specific clinical phenotypes [3]. The failure to demonstrate specific clinical outcomes in our earlier dataset might be attributable to comparing genetically heterogeneous M. tuberculosis complex main lineages; this could have confounded our results thereby suggesting no difference in virulence. Differences in bacterial characteristics have provided insight into how the M. tuberculosis complex bacteria cause disease, and why some are geographically wide spread. For instance, the Beijing strains that belong to M. tuberculosis lineage 2 are highly virulent, prone to drug resistance and BCG vaccination is not protective. This may partly explain why they are a global threat [1215]. Additionally, strains of M. tuberculosis lineage 4 are associated with pulmonary tuberculosis and severe lung consolidation, less virulent [16] and prone to anti-tuberculosis drug resistance [17] as opposed to other sub lineages. Similarly Newton et al,[18] showed that sub-lineages of M. tuberculosis lineage 3 cause severe disease; Stucki et al, [19] and Hershberg, 2016 [20] showed that M. tuberculosis lineage 5–7 have a narrow host range, thus they are restricted to particular geographical niche. Therefore, accurate understanding of M. tuberculosis complex sub-lineages and their clinical outcomes can bolster the development of appropriate intervention strategies that more effectively target the circulating strains.

Given that background in the current study, we are describing sub-lineages/sub-strains within the main M. tuberculosis lineage 3, the least dominant MTB lineage in kampala. To answer this question we shall start by analyzing the MTB direct repeat (DR) loci for sub lineages within M. tuberculosis lineage 3 as well as understanding the demographic and clinical manifestation of patients infected with MTB-L3 sub lineages. With such an approach, we can describe whether sub-lineages of M. tuberculosis lineage 3 prevalent in Kampala, Uganda differ in their ability to cause severe disease (extent of lung involvement abnormalities) as evaluated by chest x-ray.

Materials and methods

Study design and M. tuberculosis isolates

The M. tuberculosis isolates used in this study were obtained from adult (≥ 18 years) patients (index cases) and their household contacts (HHCs), confirmed with pulmonary TB by culture in a cross sectional study (2002–2012) in Kawempe division Kampala, Uganda [11, 21], where the data for the current study is coming from. The HHCs were TB patients who had stayed with an index patient for at least 7 consecutive days for the previous 3 months. The index cases residing with 1 or more HHCs were enrolled in the study through the clinic at the Uganda National TB and leprosy program at Mulago Hospital or by referral to the TB research clinic at Mulago Hospital or through public sensitization in Kawempe division. Adults with clinical signs (a positive chest x-ray or sputum smear positive) suggestive of tuberculosis provided a sputum sample for culture following standard laboratory procedures. The patients with active TB were treated using a short course therapy of Isoniazid (INH), rifampicin (RIF), pyrazinamide and ethambutol for 2 months, followed by 4 months of INH and RIF. The cultured samples were later tested for drug resistance, patients with resistant MTB isolates were provided with treatment according to the TB program guidelines. The HHCs ≤ 5 years old, HIV and TST-positive were prophylactically treated with INH for 6–9 months. Patients’ baseline demographic and clinical variables such age, sex, HIV status, employment status, status on income, TB cavitation on chest x-ray (present or absent), ethnicity (Bantu & others), status of smoking, body mass index (BMI) calculated from height & weight, alcohol drinking, presence of BCG scar, whether patients have night sweats, knowledge of TB in the past, presenting with hemoptysis (cough with blood), having swollen lymph nodes (lymphadenitis), evaluation of extent of lung involvement on chest radiography (classified as normal, mild, moderate, or far advanced) and smear status (positive or negative), were recorded by a medical physician or a laboratory technician.

Genomic DNA extraction and genotyping M. tuberculosis isolates

DNA extraction for 141 M. tuberculosis isolates and SNP (lineage-specific SNP for M. tuberculosis lineage 3: Rv0129c_0472n) typing to identify M. tuberculosis lineage 3 was performed as described by Wampande et al, [11]. To determine the sub-lineages of M. tuberculosis lineages 3, the isolates were further analyzed with a spoligotyping commercial kit as described by Kamerbeek et al, [22], the shared international type (SIT) spoligotyping were assigned according to SITVIT and SITVIT2 database [8, 23].

Statistical analysis

Baseline variables were given as means, median if continuous while the categorical variables were described in percentages. The outcome of our analysis was a patient with minimal (lung infiltrates of slight to moderate density and disease present to a small portion of one or both lungs with no cavitation) or advanced disease (lesions more extensive than minimal disease with cavitation) on chest x-ray examination [24]. Univariate analysis was perfomed and the chi square test or Fisher’s exact test was used to compare the distribution of categorical variable by disease. Variables in univariate analyis with P ≤ 0. 2; except HIV a known risk factor for TB, were included in the multivariable logistic model. Multivariable logistic regression was used to evaluate the association between sub-lineages (sub strains) of M. tuberculosis lineage 3 (independent variable) and extent of lung involvement (minimal or advanced) disease on chest x-ray (dependent variable). The 2 individuals infected with CAS were excluded from the analysis because of the small number. Age, sex, smear status, HIV status, BCG scar, smoking status, swollen lymph nodes (lymphadenitis) and BMI were used as adjusters. All analyses were conducted with Stata software, version 12 (StataCorp, College Station, Texas).


The institutional review boards and ethics committees at University Hospitals of Cleveland, Makerere University, and the National HIV/AIDS Research Committee as well as the Uganda National Council for Science and Technology approved the study protocols. All patients gave written informed consent for study participation, including pre- and post- HIV test counseling.


In the parent study we genotyped 1286 isolates of these 11% (141/1286) were MTB lineage 3. Of the 141 patients with pulmonary tuberculosis and infected with M. tuberculosis lineages 3, 77 (55%) were infected with CAS 1-Dehli, 22 (16%) were infected with CAS 1-Kili, 10 (7%) were infected with CAS 2, 2 (1%) were infected with CAS and the rest 30 (21%) were infected with M. tuberculosis lineage 3 sub lineages not yet defined in the SIT/VIT2 spoligotype database [8] (Fig 1 & S1 Table). The most frequent SITs were SIT26 30% (43/141) followed by SIT21 16% (23/141), SIT25 11% (16/141), while the rest were ≤ 7%, those considered as orphans were 12% (17/141) (S1 Table and S2 Table).

<h2>Sub-lineages of <i>M</i>. <i>tuberculosis</i> lineage 3.</h2>
Fig. 1.

Sub-lineages of M. tuberculosis lineage 3.

The sub-lineages were identified by spoligotyping as described in Materials and Methods, N = 141.

Demographic and clinical characteristics of the study participants

For the analysis we included 141 M. tuberculosis lineage 3 isolates, each corresponding to a tuberculosis patient.

The description of the patients demographic and clinical characteristics has been detailed in Table 1; the proportions of the patients’ characteristics for the different variables among the sub-lineages of M. tuberculosis lineages 3 (Table 1) were generally similar irrespective of the MTB sub-lineage. From now onwards we have excluded the CAS strains in the analysis due to a small number (2 strains).

Tab. 1.

Participant characteristics infected with different M. tuberculosis sub lineages.

<h2>Participant characteristics infected with different <i>M. tuberculosis</i> sub lineages.</h2>

Risk factors associated with MTB lineage 3 infections

In all the analyses, CAS1-Dehli was used as the reference since is the most prevalent, and we set out to understand why it is dominant in comparison with other sub lineages circulating in the study area. Univariate analysis showed that disease severity (extent of lung involvement: minimal versus advanced disease) was not associated with any of the sub-lineages of M. tuberculosis lineage 3 (P≥ 0.05).

Risk factors such as sex (OR = 2.79; CI 95% = 1.408–5.564), smear status (OR = 4.35; CI 95% = 1.849–10.231), cavitary TB (OR = 11.667; CI 95% = 4.863–27.991), and smoking status (OR = 2.865; CI 95% = 1.331–6.16), were significantly associated with advanced severe disease. Presence of BCG scar was protective (OR = 0.326; CI 95% = 0.153–0.691). Others variables, for instance age, HIV status, alcohol drinking, tribe, coughing, fever, night sweats, BMI (under weight = <18.5 kg/m2, normal weight = ≥18.5–25 kg/m2), lymphadenitis, employment status, income and history of TB in the past are not associated with (P≥ 0.05) severe TB disease (Table 2).

Tab. 2.

Univariate analysis for odds of developing severe disease based on extent of disease on chest x-ray.

<h2>Univariate analysis for odds of developing severe disease based on extent of disease on chest x-ray.</h2>

Multivariable analysis for association between severe lung disease and sub lineages of M. tuberculosis lineage 3

In the multivariate analysis after adjusting for sex, smear status, HIV status, BCG scar, smoking status and lymphadenitis, the data suggests that severity of TB disease is not dependent on the M. tuberculosis sub lineages (P ≥ 0.05).

Risk factors independently associated with disease severity included having a positive smear on sputum analysis (OR = 9.384; CI 95% = 2.603–33.835): HIV patients (OR = 0.316; CI 95% = 0.114–0.876), patients with lymphadenitis (OR = 0. 171; CI 95% = 0.034–0.856) and those with a BCG scar (OR = 0.295; CI 95% = 0.102–0.854) are less likely to have a severe TB disease (Table 3).

Tab. 3.

Multivariable analysis for odds of developing severe disease.

<h2>Multivariable analysis for odds of developing severe disease.</h2>


M. tuberculosis infections are of global concern, therefore understanding the drivers of disease progress and spread is paramount. Host and environment factors have been suggested as key players among others that can bolster TB spread, there is also overwhelming evidence that bacterial diversity of M. tuberculosis may impact the dynamics of TB outcomes among those patients infected with the bacteria [16]. In the current study, we sought to determine whether sub-lineage variations within M. tuberculosis lineage 3 could influence disease severity outcome. Firstly, we characterized the sub-lineages within the main M. tuberculosis lineage 3 circulating in central Kampala. Secondly, we investigated for the clinical and epidemiological risk factors associated with sub-lineage infections. Such data is important in designing appropriate strategies for the management of TB.

In our study, among sub-lineages of M. tuberculosis lineage 3, the most successful sub-lineage was CAS 1-Dehli that causes at least 50% of the pulmonary TB, followed by CAS 1-Kili and CAS. This current data is contrary to earlier findings by Asiimwe et al, [25] in central Uganda, who showed that CAS 1-Kili was the most prevalent sub-strain, yet Bazira et al, [26] in western Uganda observed only CAS-Dehli sub-strains. In another study that exclusively considered extra pulmonary TB showed CAS 1-Dehli as the most prevalent, the previous 2 studies compares well with the current data [27]. Despite these incongruences, we argue our data is more robust since spoligotyping was performed on isolates that were first confirmed as M. tuberculosis lineage 3 by SNP [7] typing. The approach of defining first the main MTB lineage by SNP typing reduces on the errors of misclassifying intra lineage sub strains by spoligotyping since the direct repeat loci is prone to convergent evolution [6]. The other studies described exclusively used spoligotyping technique alone to define the sub lineages, and this could result in misclassification of sub lineages due to convergent evolution, thereby impacting the data. Moreover, in addition to MTB-L3 sub lineages, they considered other MTB lineages in the same study, which can disproportionately misrepresent the status quo due to overrepresentation of other sub lineages in the study area [11, 28]. Our current data demonstrated quite a number of isolates, 21% (30/141) that could not be classified in any of the known sub lineage. This finding leads one to consider that these might be unknown strains. Nevertheless, we cannot rule out the possibility of mixed (having more than one sub lineage) infections in patients as earlier reported by Dickman et al, [29] who studied isolates from the same study area. Such a scenario produces muddled finger prints which cannot be ascribed to any of the known shared international type (SIT) spoligotypes in the SITVIT2 database. Efforts are underway to fully characterize these supposedly “unknown strains” and have them undoubtedly described to the M. tuberculosis research community.

From our current data, to assess why CAS 1-Dehli is the most successful sub lineage in causing disease, we hypothesized that sub-lineages within M. tuberculosis lineage 3 differ in their ability of causing advanced severe disease; we defined severe disease as extent of lung engrossment with TB specific lesions and cavitation (minimal or advanced disease) on chest x-ray. Our data shows that the M. tuberculosis sub-lineages circulating in central Uganda equally cause disease in the infected patients (P ≥ 0.05). The CAS-sub-lineage suggests an association with severe disease (aOR = 5.9; aCI = 0.36–95.76), but then again due to the small sample size the wide confidence interval does not support the finding, this calls for another bigger study to substantiate on this observation. Contrary to our findings, M. tuberculosis lineage 3 sub strain infections have been associated with different phenotypes for instance, reduced expression of TNFα and IFNγ, reduced growth rate in macrophages [18, 30], causing cavitary TB, pan sensitivity to anti-TB drugs [31] and causing severe disease [18]. Noticeably, TB household population studies can be confounded by a number of factors that could have affected our downward data analysis [32]. Nonetheless, we think our analysis was robust enough since known risk factors, such as patients with a positive smear (OR = 9. 384; CI 95% = 2.603–33.835) were associated with severe disease, HIV reduces (OR = 0.316; CI 95% = 0.114–0.876) the risk of developing severe disease [33, 34]. Additionally, the data showed that patients with BCG scar (OR = 0.295; CI 95% = 0.102–0.854) and swollen lymph nodes (lymphadenitis) were less likely to develop advanced severe disease. Presence of scar on the shoulders suggests that the patients were vaccinated with a BCG vaccine. The efficacy of the BCG vaccine has been found to be variable in conferring protection against M. tuberculosis infection [35, 36]. For instance BCG vaccination is not protective to M. tuberculosis Beijing (MTB lineage 2) strains [12, 37], but is protective of lineage 4 (H37RV, Harlem) and M. canetti strains [38]. This data therefore suggests that BCG vaccination might be protective against the development of advance severe disease in M. tuberculosis lineage 3 sub strains infections. Whether this is true between lineages, another study can elucidate on this observation. In addition, the data suggests that patients with lymphadenitis (OR = 0.171; CI 95% = 0.034–0.856) are less likely to develop severe disease. This could be for two reasons; perhaps patients had other infections that caused the lymphadenitis and not M. tuberculosis lineage 3 infections per say. Secondly, trafficking of M. tuberculosis from the primary foci (most often the lung depending on the route of infection) to the regional lymph nodes causes inflammation and subsequent localization of the bacillus in the lymphatic tissues a scenario referred to as extra pulmonary tuberculosis. Studies have demonstrated that M. tuberculosis sub lineages preferentially targets pulmonary (lungs) or extra pulmonary tissues (lymph nodes, bones, intestines, meninges among others) [39, 40]. For instance, the Euro American lineage is associated with pulmonary tuberculosis [41], Beijing strains are associated with severe lung pathology [15], the East Africa India strains cause a less severe pulmonary disease [42] and CAS strains are more prevalent in extra pulmonary tuberculosis infections [27, 43].


Because MTB-L3 is not common in Uganda, our analyses of the sub lineages were limited by sample size, resulting in large confidence intervals and a potential loss of statistical power. Secondly, there was a selection bias (index patient) in recruitment of the patients which could inherently skew the findings. Thirdly, the study did not explore the possibilities of other comorbid diseases among the TB patients which could impact our results. Our approach could have been inferior to other genotyping techniques such MIRU-VNTR, whole genome sequencing in resolving sub lineages. However, the strength of this study is that we used a robust SNP typing assay to delineate MTB- main lineages 3, this improves on the accuracy of defining the sub lineages.


In Kampala, Uganda, there are sub lineages of M. tuberculosis lineage 3, of which CAS-Dehli is the most predominant. None of these is associated with increased risk of causing severe disease. Patients infected with M. tuberculosis lineage 3 strains who have lymphadenitis or have a BCG scar are less likely to develop severe disease; patients with a positive smear have a higher risk of developing severe disease”

Supporting information

S1 Table [docx]
Spoligotype pattern of . lineage 3 strains.

S2 Table [docx]
. lineage 3 strains spoligotypes with unknown shared international type numbers (SIT #).


1. Brites D, Gagneux S. Co-evolution of Mycobacterium tuberculosis and Homo sapiens. Immunological reviews. 2015;264(1):6–24. doi: 10.1111/imr.12264 25703549; PubMed Central PMCID: PMC4339235.

2. Firdessa R, Berg S, Hailu E, Schelling E, Gumi B, Erenso G, et al. Mycobacterial lineages causing pulmonary and extrapulmonary tuberculosis, Ethiopia. Emerging infectious diseases. 2013;19(3):460–3. doi: 10.3201/eid1903.120256 23622814; PubMed Central PMCID: PMC3647644.

3. Coscolla M, Gagneux S. Consequences of genomic diversity in Mycobacterium tuberculosis. Seminars in immunology. 2014;26(6):431–44. doi: 10.1016/j.smim.2014.09.012 25453224; PubMed Central PMCID: PMC4314449.

4. Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(8):2869–73. doi: 10.1073/pnas.0511240103 16477032; PubMed Central PMCID: PMC1413851.

5. Gagneux S, Small PM. Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development. The Lancet Infectious diseases. 2007;7(5):328–37. doi: 10.1016/S1473-3099(07)70108-1 17448936.

6. Comas I, Homolka S, Niemann S, Gagneux S. Genotyping of genetically monomorphic bacteria: DNA sequencing in Mycobacterium tuberculosis highlights the limitations of current methodologies. PloS one. 2009;4(11):e7815. doi: 10.1371/journal.pone.0007815 19915672; PubMed Central PMCID: PMC2772813.

7. Wampande EM, Hatzios SK, Achan B, Mupere E, Nsereko M, Mayanja HK, et al. A single-nucleotide-polymorphism real-time PCR assay for genotyping of Mycobacterium tuberculosis complex in peri-urban Kampala. BMC infectious diseases. 2015;15:396. doi: 10.1186/s12879-015-1121-7 26423522; PubMed Central PMCID: PMC4590274.

8. Brudey K, Driscoll JR, Rigouts L, Prodinger WM, Gori A, Al-Hajoj SA, et al. Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology. BMC microbiology. 2006;6:23. doi: 10.1186/1471-2180-6-23 16519816; PubMed Central PMCID: PMC1468417.

9. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nature genetics. 2013;45(10):1176–82. doi: 10.1038/ng.2744 23995134; PubMed Central PMCID: PMC3800747.

10. Brites D, Gagneux S. Old and new selective pressures on Mycobacterium tuberculosis. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2012;12(4):678–85. doi: 10.1016/j.meegid.2011.08.010 21867778; PubMed Central PMCID: PMC3253320.

11. Wampande EM, Mupere E, Debanne SM, Asiimwe BB, Nsereko M, Mayanja H, et al. Long-term dominance of Mycobacterium tuberculosis Uganda family in peri-urban Kampala-Uganda is not associated with cavitary disease. BMC infectious diseases. 2013;13:484. doi: 10.1186/1471-2334-13-484 24134504; PubMed Central PMCID: PMC3853102.

12. Parwati I, van Crevel R, van Soolingen D. Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. The Lancet Infectious diseases. 2010;10(2):103–11. doi: 10.1016/S1473-3099(09)70330-5 20113979.

13. Ordway D, Henao-Tamayo M, Shanley C, Smith EE, Palanisamy G, Wang B, et al. Influence of Mycobacterium bovis BCG vaccination on cellular immune response of guinea pigs challenged with Mycobacterium tuberculosis. Clinical and vaccine immunology: CVI. 2008;15(8):1248–58. doi: 10.1128/CVI.00019-08 18508930; PubMed Central PMCID: PMC2519313.

14. Ordway DJ, Shang S, Henao-Tamayo M, Obregon-Henao A, Nold L, Caraway M, et al. Mycobacterium bovis BCG-mediated protection against W-Beijing strains of Mycobacterium tuberculosis is diminished concomitant with the emergence of regulatory T cells. Clinical and vaccine immunology: CVI. 2011;18(9):1527–35. doi: 10.1128/CVI.05127-11 21795460; PubMed Central PMCID: PMC3165219.

15. Kato-Maeda M, Shanley CA, Ackart D, Jarlsberg LG, Shang S, Obregon-Henao A, et al. Beijing sublineages of Mycobacterium tuberculosis differ in pathogenicity in the guinea pig. Clinical and vaccine immunology: CVI. 2012;19(8):1227–37. doi: 10.1128/CVI.00250-12 22718126; PubMed Central PMCID: PMC3416080.

16. Coscolla M, Gagneux S. Does M. tuberculosis genomic diversity explain disease diversity? Drug discovery today Disease mechanisms. 2010;7(1):e43–e59. doi: 10.1016/j.ddmec.2010.09.004 21076640; PubMed Central PMCID: PMC2976975.

17. Lukoye D, Katabazi FA, Musisi K, Kateete DP, Asiimwe BB, Okee M, et al. The T2 Mycobacterium tuberculosis genotype, predominant in Kampala, Uganda, shows negative correlation with antituberculosis drug resistance. Antimicrobial agents and chemotherapy. 2014;58(7):3853–9. doi: 10.1128/AAC.02338-13 24777100; PubMed Central PMCID: PMC4068514.

18. Newton SM, Smith RJ, Wilkinson KA, Nicol MP, Garton NJ, Staples KJ, et al. A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(42):15594–8. doi: 10.1073/pnas.0604283103 17028173; PubMed Central PMCID: PMC1622867.

19. Stucki D, Brites D, Jeljeli L, Coscolla M, Liu Q, Trauner A, et al. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages. Nature genetics. 2016;48(12):1535–43. doi: 10.1038/ng.3704 27798628; PubMed Central PMCID: PMC5238942.

20. Hershberg R. Human host range of Mycobacterium tuberculosis. Nature genetics. 2016;48(12):1453–4. doi: 10.1038/ng.3724 27898082

21. Stein CM, Zalwango S, Malone LL, Thiel B, Mupere E, Nsereko M, et al. Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda. American journal of epidemiology. 2018;187(7):1477–89. doi: 10.1093/aje/kwx380 29304247; PubMed Central PMCID: PMC6031055.

22. Kamerbeek J, Schouls L, Kolk A, van Agterveld M, van Soolingen D, Kuijper S, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. Journal of clinical microbiology. 1997;35(4):907–14. 9157152; PubMed Central PMCID: PMC229700.

23. Couvin D, David A, Zozio T, Rastogi N. Macro-geographical specificities of the prevailing tuberculosis epidemic as seen through SITVIT2, an updated version of the Mycobacterium tuberculosis genotyping database. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2018. doi: 10.1016/j.meegid.2018.12.030 30593925.

24. Falk AP P.C. Classification of pulmonary tuberculosis. Diagnosis standards and classification of tuberculosis. Edited by: Falk A, O'Connor AJB, Pratt PC, Webb JA, Weir JA, Wolinsky A. 1969, New York, NY: National Tuberculosis and Respiratory Disease Association, 12: 68–76.

25. Asiimwe BB, Ghebremichael S, Kallenius G, Koivula T, Joloba ML. Mycobacterium tuberculosis spoligotypes and drug susceptibility pattern of isolates from tuberculosis patients in peri-urban Kampala, Uganda. BMC infectious diseases. 2008;8:101. doi: 10.1186/1471-2334-8-101 PubMed Central PMCID: PMC2519071. 18662405

26. Bazira J, Asiimwe BB, Joloba ML, Bwanga F, Matee MI. Mycobacterium tuberculosis spoligotypes and drug susceptibility pattern of isolates from tuberculosis patients in South-Western Uganda. BMC infectious diseases. 2011;11:81. doi: 10.1186/1471-2334-11-81 21453482; PubMed Central PMCID: PMC3100262.

27. Wamala D, Okee M, Kigozi E, Couvin D, Rastogi N, Joloba M, et al. Predominance of Uganda genotype of Mycobacterium tuberculosis isolated from Ugandan patients with tuberculous lymphadenitis. BMC research notes. 2015;8:398. doi: 10.1186/s13104-015-1362-y 26323435; PubMed Central PMCID: PMC4556223.

28. Asiimwe BB, Koivula T, Kallenius G, Huard RC, Ghebremichael S, Asiimwe J, et al. Mycobacterium tuberculosis Uganda genotype is the predominant cause of TB in Kampala, Uganda. The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease. 2008;12(4):386–91. 18371263.

29. Dickman KR, Nabyonga L, Kateete DP, Katabazi FA, Asiimwe BB, Mayanja HK, et al. Detection of multiple strains of Mycobacterium tuberculosis using MIRU-VNTR in patients with pulmonary tuberculosis in Kampala, Uganda. BMC infectious diseases. 2010;10:349. doi: 10.1186/1471-2334-10-349 21143966; PubMed Central PMCID: PMC3004912.

30. Tanveer M, Hasan Z, Kanji A, Hussain R, Hasan R. Reduced TNF-alpha and IFN-gamma responses to Central Asian strain 1 and Beijing isolates of Mycobacterium tuberculosis in comparison with H37Rv strain. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2009;103(6):581–7. doi: 10.1016/j.trstmh.2009.03.014 19375139.

31. Chatterjee A, D'Souza D, Vira T, Bamne A, Ambe GT, Nicol MP, et al. Strains of Mycobacterium tuberculosis from western Maharashtra, India, exhibit a high degree of diversity and strain-specific associations with drug resistance, cavitary disease, and treatment failure. Journal of clinical microbiology. 2010;48(10):3593–9. doi: 10.1128/JCM.00430-10 20720028; PubMed Central PMCID: PMC2953068.

32. Malik AN, Godfrey-Faussett P. Effects of genetic variability of Mycobacterium tuberculosis strains on the presentation of disease. The Lancet Infectious diseases. 2005;5(3):174–83. doi: 10.1016/S1473-3099(05)01310-1 15766652.

33. Aderaye G, Bruchfeld J, Assefa G, Feleke D, Kallenius G, Baat M, et al. The relationship between disease pattern and disease burden by chest radiography, M. tuberculosis Load, and HIV status in patients with pulmonary tuberculosis in Addis Ababa. Infection. 2004;32(6):333–8. doi: 10.1007/s15010-004-3089-x 15597222.

34. Altet-Gomez MN, Alcaide J, Godoy P, Romero MA, Hernandez del Rey I. Clinical and epidemiological aspects of smoking and tuberculosis: a study of 13,038 cases. The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease. 2005;9(4):430–6. 15830749.

35. Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PE, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2014;58(4):470–80. doi: 10.1093/cid/cit790 24336911.

36. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. Bmj. 2014;349:g4643. doi: 10.1136/bmj.g4643 25097193; PubMed Central PMCID: PMC4122754.

37. van Soolingen D, Qian L, de Haas PE, Douglas JT, Traore H, Portaels F, et al. Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia. Journal of clinical microbiology. 1995;33(12):3234–8. 8586708; PubMed Central PMCID: PMC228679.

38. Lopez B, Aguilar D, Orozco H, Burger M, Espitia C, Ritacco V, et al. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clinical and experimental immunology. 2003;133(1):30–7. doi: 10.1046/j.1365-2249.2003.02171.x 12823275; PubMed Central PMCID: PMC1808750.

39. Click ES, Moonan PK, Winston CA, Cowan LS, Oeltmann JE. Relationship between Mycobacterium tuberculosis phylogenetic lineage and clinical site of tuberculosis. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2012;54(2):211–9. doi: 10.1093/cid/cir788 22198989.

40. Srilohasin P, Chaiprasert A, Tokunaga K, Nishida N, Prammananan T, Smittipat N, et al. Genetic diversity and dynamic distribution of Mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in Thailand. Journal of clinical microbiology. 2014;52(12):4267–74. doi: 10.1128/JCM.01467-14 25297330; PubMed Central PMCID: PMC4313297.

41. Caws M, Thwaites G, Dunstan S, Hawn TR, Lan NT, Thuong NT, et al. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS pathogens. 2008;4(3):e1000034. doi: 10.1371/journal.ppat.1000034 18369480; PubMed Central PMCID: PMC2268004.

42. Albanna AS, Reed MB, Kotar KV, Fallow A, McIntosh FA, Behr MA, et al. Reduced transmissibility of East African Indian strains of Mycobacterium tuberculosis. PloS one. 2011;6(9):e25075. doi: 10.1371/journal.pone.0025075 21949856; PubMed Central PMCID: PMC3176299.

43. Sankar MM, Singh J, Diana SC, Singh S. Molecular characterization of Mycobacterium tuberculosis isolates from North Indian patients with extrapulmonary tuberculosis. Tuberculosis. 2013;93(1):75–83. doi: 10.1016/ 23140853.

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2019 Číslo 9