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Browsing by Author "Warren, Rob"

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Automated IS6110-based fingerprinting of Mycobacterium tuberculosis : reaching unprecedented discriminatory power and versatility
(Public Library of Science, 2018) Dekhil, Naira; Skhairia, Mohamed Amine; Mhenni, Besma; Fradj, Saloua Ben; Warren, Rob; Mardassi, Helmi
Background: Several technical hurdles and limitations have restricted the use of IS6110 restriction fragment length polymorphism (IS6110 RFLP), the most effective typing method for detecting recent tuberculosis (TB) transmission events. This has prompted us to conceive an alternative modality, IS6110-5’3’FP, a plasmid-based cloning approach coupled to a single PCR amplification of differentially labeled 5’ and 3’ IS6110 polymorphic ends and their automated fractionation on a capillary sequencer. The potential of IS6110-5’3’FP to be used as an alternative to IS6110 RFLP has been previously demonstrated, yet further technical improvements are still required for optimal discriminatory power and versatility. Objectives: Here we introduced critical amendments to the original IS6110-5’3’FP protocol and compared its performance to that of 24-loci multiple interspersed repetitive unit-variable number tandem repeats (MIRU-VNTR), the current standard method for TB transmission analyses. Methods: IS6110-5’3’FP protocol modifications involved: (i) the generation of smaller-sized polymorphic fragments for efficient cloning and PCR amplification, (ii) omission of the plasmid amplification step in E. coli for shorter turnaround times, (iii) the use of more stable fluorophores for increased sensitivity, (iv) automated subtraction of background fluorescent signals, and (v) the automated conversion of fluorescent peaks into binary data. Results: In doing so, the overall turnaround time of IS6110-5’3’FP was reduced to 4 hours. The new protocol allowed detecting almost all 5’ and 3’ IS6110 polymorphic fragments of any given strain, including IS6110 high-copy number Beijing strains. IS6110-5’3’FP proved much more discriminative than 24-loci MIRU-VNTR, particularly with strains of the M. tuberculosis lineage 4. Conclusions: The IS6110-5’3’FP protocol described herein reached the optimal discriminatory potential of IS6110 fingerprinting and proved more accurate than 24-loci MIRU-VNTR in estimating recent TB transmission. The method, which is highly cost-effective, was rendered versatile enough to prompt its evaluation as an automatized solution for a TB integrated molecular surveillance.
Baseline predictors of sputum culture conversion in pulmonary tuberculosis : importance of cavities, smoking, time to detection and W-Beijing genotype
(PLOS, 2012-01-04) Visser, Marianne E.; Stead, Michael C.; Walzl, Gerhard; Warren, Rob; Schomaker, Michael; Grewal, Harleen M. S.; Swart, Elizabeth C.; Maartens, Gary
Background: Time to detection (TTD) on automated liquid mycobacterial cultures is an emerging biomarker of tuberculosis outcomes. The M. tuberculosis W-Beijing genotype is spreading globally, indicating a selective advantage. There is a paucity of data on the association between baseline TTD and W-Beijing genotype and tuberculosis outcomes. Aim: To assess baseline predictors of failure of sputum culture conversion, within the first 2 months of antitubercular therapy, in participants with pulmonary tuberculosis. Design: Between May 2005 and August 2008 we conducted a prospective cohort study of time to sputum culture conversion in ambulatory participants with first episodes of smear and culture positive pulmonary tuberculosis attending two primary care clinics in Cape Town, South Africa. Rifampicin resistance (diagnosed on phenotypic susceptibility testing) was an exclusion criterion. Sputum was collected weekly for 8 weeks for mycobacterial culture on liquid media (BACTEC MGIT 960). Due to missing data, multiple imputation was performed. Time to sputum culture conversion was analysed using a Cox-proportional hazards model. Bayesian model averaging determined the posterior effect probability for each variable. Results: 113 participants were enrolled (30.1% female, 10.5% HIV-infected, 44.2% W-Beijing genotype, and 89% cavities). On Kaplan Meier analysis 50.4% of participants underwent sputum culture conversion by 8 weeks. The following baseline factors were associated with slower sputum culture conversion: TTD (adjusted hazard ratio (aHR) = 1.11, 95% CI 1.02; 1.2), lung cavities (aHR = 0.13, 95% CI 0.02; 0.95), ever smoking (aHR = 0.32, 95% CI 0.1; 1.02) and the W-Beijing genotype (aHR = 0.51, 95% CI 0.25; 1.07). On Bayesian model averaging, posterior probability effects were strong for TTD, lung cavitation and smoking and moderate for W-Beijing genotype. Conclusion: We found that baseline TTD, smoking, cavities and W-Beijing genotype were associated with delayed 2 month sputum culture. Larger studies are needed to confirm the relationship between the W-Beijing genotype and sputum culture conversion.
Bedaquiline microheteroresistance after cessation of tuberculosis treatment
(Massachusetts Medical Society, 2019-05-30) De Vos, Margaretha; Wiggins, Kristin B.; Derendinger, Brigitta; Reuter, Anja; Dolby, Tania; Burns, Scott; Schito, Marco; Engelthaler, David M.; Metcalfe, John; Theron, Grant; Van Rie, Annelies; Posey, James; Warren, Rob; Cox, Helen
ENGLISH ABSTRACT: Bedaquiline improves survival among persons with multidrug-resistant tuberculosis (MDR-TB).1 We report the case of a 65-year-old South African man who was negative for human immunodeficiency virus and in whom MDR-TB was diagnosed in 2013 (resistant to rifampin and isoniazid; phenotypically susceptible to a fluoroquinolone and amikacin). A baseline radiograph showed changes consistent with bilateral tuberculosis with left apex cavitation. He started standardized treatment that included moxifloxacin, pyrazinamide, kanamycin, ethionamide, isoniazid, and terizidone. After initial sputum culture conversion (at month 3) and clinical improvement, the patient again became culture-positive, and bilateral cavitation developed. After detection of phenotypic resistance to fluoroquinolones (at month 6), his treatment was revised (at month 8) to include high-dose isoniazid, ethambutol, pyrazinamide, terizidone, linezolid, paraaminosalicylic acid, and kanamycin (Figure 1 and the Supplementary Appendix, available with the full text of this letter at NEJM.org). Bedaquiline was added 22 days later and was administered for 6 months.2 The patient remained culture-positive (treatment failure), and treatment was stopped 15 months after revision of the regimen. The patient died 7 months later.
Bovine tuberculosis in African buffaloes : observations regarding Mycobacterium bovis shedding into water and exposure to environmental mycobacteria
(BioMed Central, 2007-09) Michel, Anita L.; De Klerk, Lin-Mari; Gey van Pittius, Nico C.; Warren, Rob; Van Helden, Paul D.
Background: African buffaloes are the maintenance host for Mycobacterium bovis in the endemically infected Kruger National Park (KNP). The infection is primarily spread between buffaloes via the respiratory route, but it is not known whether shedding of M. bovis in nasal and oral excretions may lead to contamination of ground and surface water and facilitate the transmission to other animal species. A study to investigate the possibility of water contamination with M. bovis was conducted in association with a BCG vaccination trial in African buffalo. Groups of vaccinated and nonvaccinated buffaloes were kept together with known infected in-contact buffalo cows to allow natural M. bovis transmission under semi-free ranging conditions. In the absence of horizontal transmission vaccinated and control buffaloes were experimentally challenged with M. bovis. Hence, all study buffaloes in the vaccination trial could be considered potential shedders and provided a suitable setting for investigating questions relating to the tenacity of M. bovis shed in water. Results: Serial water samples were collected from the drinking troughs of the buffaloes once per season over an eleven-month period and cultured for presence of mycobacteria. All water samples were found to be negative for M. bovis, but 16 non-tuberculous Mycobacterium spp. isolates were cultured. The non-tuberculous Mycobacterium species were further characterised using 5'-16S rDNA PCR-sequencing, resulting in the identification of M. terrae, M. vaccae (or vanbaalenii), M. engbaekii, M. thermoresistibile as well as at least two species which have not yet been classified. Conclusion: The absence of detectable levels of Mycobacterium bovis in the trough water suggests that diseased buffalo do not commonly shed the organism in high quantities in nasal and oral discharges. Surface water may therefore not be likely to play an important role in the transmission of bovine tuberculosis from buffalo living in free-ranging ecosystems. The study buffalo were, however, frequently exposed to different species of non-tuberculous, environmental mycobacteria, with an unknown effect on the buffaloes' immune response to mycobacteria.
Comparison of quantitative techniques including Xpert MTB/RIF to evaluate mycobacterial burden
(PLOS, 2011-12) Van Zyl-Smit, Richard N.; Binder, Anke; Meldau, Richard; Mishra, H.; Semple, P. L.; Theron, G.; Peter, J.; Whitelaw, A.; Sharma, S. K.; Warren, Rob; Bateman, E. D.; Dheda, K.
Introduction: Accurate quantification of mycobacterial load is important for the evaluation of patient infectiousness, disease severity and monitoring treatment response in human and in-vitro laboratory models of disease. We hypothesized that newer techniques would perform as well as solid media culture to quantify mycobacterial burden in laboratory specimens. Methods: We compared the turn-around-time, detection-threshold, dynamic range, reproducibility, relative discriminative ability, of 4 mycobacterial load determination techniques: automated liquid culture (BACTEC-MGIT-960), [3H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative PCR(Xpert -MTB/RIF) using serial dilutions of Mycobacterium bovis and Mycobacterium tuberculosis H37RV. Mycobacterial colony-forming-units(CFU) using 7H10-Middlebrook solid media served as the reference standard. Results: All 4 assays correlated well with the reference standard, however, bioluminescence and uracil assays had a detection threshold $16103 organisms. By contrast, BACTEC-MGIT-960 liquid culture, although only providing results in days, was user-friendly, had the lowest detection threshold (,10 organisms), the greatest discriminative ability (1 vs. 10 organisms; p = 0.02), and the best reproducibility (coefficient of variance of 2% vs. 38% compared to uracil incorporation; p = 0.02). Xpert-MTB/RIF correlated well with mycobacterial load, had a rapid turn-around-time (,2 hours), was user friendly, but had a detection limit of ,100 organisms. Conclusions: Choosing a technique to quantify mycobacterial burden for laboratory or clinical research depends on availability of resources and the question being addressed. Automated liquid culture has good discriminative ability and low detection threshold but results are only obtained in days. Xpert MTB/RIF provides rapid quantification of mycobacterial burden, but has a poorer discrimination and detection threshold.
The diagnostic accuracy of the MTBDRplus and MTBDRsl assays for drug-resistant TB detection when performed on sputum and culture isolates
(Springer Nature, 2016) Tomasicchio, Michele; Theron, Grant; Pietersen, Elize; Streicher, Elizabeth M.; Stanley-Josephs, Danielle; Van Helden, Paul; Warren, Rob; Dheda, Keertan
Although molecular tests for drug-resistant TB perform well on culture isolates, their accuracy using clinical samples, particularly from TB and HIV-endemic settings, requires clarification. The MTBDRplus and MTBDRsl line probe assays were evaluated in 181 sputum samples and 270 isolates from patients with culture-confirmed drug-sensitive-TB, MDR-TB, or XDR-TB. Phenotypic culture-based testing was the reference standard. Using sputum, the sensitivities for resistance was 97.7%, 95.4%, 58.9%, 61.6% for rifampicin, isoniazid, ofloxacin, and amikacin, respectively, whereas the specificities were 91.8%, 89%, 100%, and 100%, respectively. MTBDRsl sensitivity differed in smear-positive vs. smear-negative samples (79.2% vs. 20%, p < 0.0001 for ofloxacin; 72.9% vs. 37%, p = 0.0023 for amikacin) but not by HIV status. If used sequentially, MTBDRplus and MTBDRsl could rule-in XDR-TB in 78.5% (22/28) and 10.5% (2/19) of smear-positive and smear-negative samples, respectively. On culture isolates, the sensitivity for resistance to rifampicin, isoniazid, ofloxacin, and amikacin was 95.1%, 96.1%, 72.3% and 76.6%, respectively, whereas the specificities exceeded 96%. Using a sequential testing approach, rapid sputum-based diagnosis of fluoroquinolone or aminoglycoside-resistant TB is feasible only in smear-positive samples, where rule-in value is good. Further investigation is required in samples that test susceptible in order to rule-out second-line drug resistance.
Differential RD-1-specific IFN-γ host responses to diverse Mycobacterium tuberculosis strains in HIV-uninfected persons may be explained by genotypic variation in the ESX-1 region
(Elsevier, 2020-04) Tomasicchio, Michele; Limberis, Jason; van der Merwe, Ruben; Jacobson, Rachael; Meldau, Richard; Theron, Grant; Nicol, Mark; Warren, Rob; Dheda, Keertan
Objectives: Between-person variability in T-cell-specific interferon-gamma release assay (IGRA) responses and discordance between IGRA test formats are poorly understood. Methods: We evaluated the IFN-γ responses (QuantiFERON-TB Gold-In-Tube [QFT-GIT] and TSPOT-TB) stratified according to the Mycobacterium tuberculosis spoligotype of the culture isolate obtained from the same patients with confirmed active tuberculosis (n = 91). We further analysed differences within the RD-1-encoding ESX-1 region between the different strain types using whole genome sequencing. Results: In HIV-uninfected patients, TSPOT.TB and QFT-GIT IFN-γ responses were 5-fold (p < 0.01) and 2-fold higher (p < 0.05) for those infected with family 33 compared to the LAM strain (additionally, TSPOT.TB responses were 5.6-fold [p < 0.05] and 2.6-fold higher [p < 0.05] for the patients infected with the family 33 versus the X strain and Beijing versus the LAM strain, respectively). Multivariate analysis revealed that strain type (determined by spoligotyping) was independently associated with the magnitude of the IGRA response (varied by IGRA test type) and this is likely explained by variability in the ESX-1 region of Mycobacteriumtuberculosis (determined by next-generation sequencing). Conclusions: These data have implications for the understanding of between-person heterogeneity in IGRA responses, Mycobateriumtuberculosis-specific host immunity, and the discordance between different IGRA test formats.
GenoType MTBDRsl assay for resistance to second-line anti-tuberculosis drugs
(Cochrane, 2016-09-08) Theron, Grant; Peter, Jonny; Richardson, Marty; Warren, Rob; Dheda, Keertan; Steingart, Karen R.
Background: Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of aWorld Health Organization process to develop updated guidelines for using MTBDRsl. Objectives: To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance.
Independent large scale duplications in multiple M. tuberculosis lineages overlapping the same genomic region
(Public Library of Science, 2012-02-07) Weiner, Brian; Gomez, James; Victor, Thomas C.; Warren, Rob; Sloutsky, Alexander; Plikaytis, Bonnie B.; Posey, James E.; Van Helden, Paul D.; Van Pittius, Nicolaas C. Gey; Koehrsen, Michael; Sisk, Peter; Stolte, Christian; White, Jared; Gagneux, Sebastian; Birren, Bruce; Hung, Deborah; Murray, Megan; Galagan, James
ENGLISH ABSTRACT: Mycobacterium tuberculosis, the causative agent of most human tuberculosis, infects one third of the world’s population and kills an estimated 1.7 million people a year. With the world-wide emergence of drug resistance, and the finding of more functional genetic diversity than previously expected, there is a renewed interest in understanding the forces driving genome evolution of this important pathogen. Genetic diversity in M. tuberculosis is dominated by single nucleotide polymorphisms and small scale gene deletion, with little or no evidence for large scale genome rearrangements seen in other bacteria. Recently, a single report described a large scale genome duplication that was suggested to be specific to the Beijing lineage. We report here multiple independent large-scale duplications of the same genomic region of M. tuberculosis detected through whole-genome sequencing. The duplications occur in strains belonging to both M. tuberculosis lineage 2 and 4, and are thus not limited to Beijing strains. The duplications occur in both drug-resistant and drug susceptible strains. The duplicated regions also have substantially different boundaries in different strains, indicating different originating duplication events. We further identify a smaller segmental duplication of a different genomic region of a lab strain of H37Rv. The presence of multiple independent duplications of the same genomic region suggests either instability in this region, a selective advantage conferred by the duplication, or both. The identified duplications suggest that large-scale gene duplication may be more common in M. tuberculosis than previously considered.
Mixed strain Mycobacterium tuberculosis infections: implications for tuberculosis treatment and control.
(AMER SOC MICROBIOLOGY, 1752 N ST NW, WASHINGTON, USA, DC, 20036-2904, 2012) Cohen, T.; Van Helden, P. D.; Wilson, D.; Colijn, C.; McLaughlin, M. M.; Abubakar, I.; Warren, Rob
Mycobacterial transport medium for routine culture of fine needle aspiration biopsies
(BMJ Publishing Group, 2010-01) Wright, C. A.; Bamford, C.; Prince, Y.; Vermaak, A.; Hoek, K. G. P.; Marais, B. J.; Warren, Rob
Fine needle aspiration biopsy (FNAB) offers a simple outpatient technique for specimen collection in child tuberculosis suspects with peripheral lymphadenopathy. To perform FNAB with mycobacterial culture on an outpatient basis requires use of a sterile transport medium to facilitate bedside inoculation, maintain organism viability and reduce contamination risk en route to the laboratory. The mycobacterial yield and time to positive culture following bedside inoculation into standard mycobacterial growth indicator tubes were compared with initial inoculation into an inexpensive "in-house" liquid growth medium. Of 150 FNAB performed, 57 (38%) cultured Mycobacterium tuberculosis complex. There was one case each with non-tuberculous mycobacteria and Mycobacterium bovis BCG; the remaining 55 being M tuberculosis. Results were concordant in 142 (94.7%) bedside and laboratory inoculation pairs. There was no significant difference in time to positive culture between bedside and laboratory inoculation (16.2 days (SD 0.87) vs 17.1 days (SD 0.85)). Provision of inexpensive specimen transport bottles and practical tuition in FNAB should improve cost-effective diagnosis of tuberculosis at the primary healthcare level.
Mycobacterium tuberculosis Beijing genotype is associated with HIV infection in Mozambique
(Public Library of Science, 2013-08-07) Viegas, Sofia O.; Machado, Adelina; Groenheit, Ramona; Ghebremichel, Solomon; Pennhag, Alexandra; Gudo, Paula S.; Cuna, Zaina; Langa, Egídio; Miotto, Paulo; Cirillo, Daniela M.; Rastogi, Nalin; Warren, Rob; Van Helden, Paul D.; Koivula, Tuija; Kullenius, Gunilla
The Beijing genotype is a lineage of Mycobacterium tuberculosis that is distributed worldwide and responsible for large epidemics, associated with multidrug-resistance. However, its distribution in Africa is less understood due to the lack of data. Our aim was to investigate the prevalence and possible transmission of Beijing strains in Mozambique by a multivariate analysis of genotypic, geographic and demographic data. A total of 543 M. tuberculosis isolates from Mozambique were spoligotyped. Of these, 33 were of the Beijing lineage. The genetic relationship between the Beijing isolates were studied by identification of genomic deletions within some Regions of Difference (RD), Restriction Fragment Length Polymorphism (RFLP) and Mycobacterial Interspersed Repetivie Unit – variable number tandem repeat (MIRU-VNTR). Beijing strains from South Africa, representing different sublineages were included as reference strains. The association between Beijing genotype, Human Immunodeficiency Virus (HIV) serology and baseline demographic data was investigated. HIV positive serostatus was significantly (p=0.023) more common in patients with Beijing strains than in patients with non-Beijing strains in a multivariable analysis adjusted for age, sex and province (14 (10.9%) of the 129 HIV positive patients had Beijing strains while 6/141 (4.3%) of HIV negative patients had Beijing strains). The majority of Beijing strains were found in the Southern region of Mozambique, particularly in Maputo City (17%). Only one Beijing strain was drug resistant (multi-drug resistant). By combined use of RD and spoligotyping, three genetic sublineages could be tentatively identified where a distinct group of four isolates had deletion of RD150, a signature of the “sublineage 7” recently emerging in South Africa. The same group was very similar to South African “sublineage 7” by RFLP and MIRU-VNTR, suggesting that this sublineage could have been recently introduced in Mozambique from South Africa, in association with HIV infection.
Phylogeny of Mycobacterium tuberculosis Beijing strains constructed from Polymorphisms in genes involved in DNA replication, recombination and repair
(Public Library of Science (PLOS), 2011-01) Mestre, Olga; Luo, Tao; Dos Vultos, Tiago; Kremer, Kristin; Murray, Alan; Namouchi, Amine; Jackson, Celine; Rauzier, Jean; Bifani, Pablo; Warren, Rob; Rasolofo, Voahangy; Mei, Jian; Gao, Qian; Gicquel, Brigitte
Background: The Beijing family is a successful group of M. tuberculosis strains, often associated with drug resistance and widely distributed throughout the world. Polymorphic genetic markers have been used to type particular M. tuberculosis strains. We recently identified a group of polymorphic DNA repair replication and recombination (3R) genes. It was shown that evolution of M. tuberculosis complex strains can be studied using 3R SNPs and a high-resolution tool for strain discrimination was developed. Here we investigated the genetic diversity and propose a phylogeny for Beijing strains by analyzing polymorphisms in 3R genes. Methodology/Principal Findings: A group of 3R genes was sequenced in a collection of Beijing strains from different geographic origins. Sequence analysis and comparison with the ones of non-Beijing strains identified several SNPs. These SNPs were used to type a larger collection of Beijing strains and allowed identification of 26 different sequence types for which a phylogeny was constructed. Phylogenetic relationships established by sequence types were in agreement with evolutionary pathways suggested by other genetic markers, such as Large Sequence Polymorphisms (LSPs). A recent Beijing genotype (Bmyc10), which included 60% of strains from distinct parts of the world, appeared to be predominant. Conclusions/Significance: We found SNPs in 3R genes associated with the Beijing family, which enabled discrimination of different groups and the proposal of a phylogeny. The Beijing family can be divided into different groups characterized by particular genetic polymorphisms that may reflect pathogenic features. These SNPs are new, potential genetic markers that may contribute to better understand the success of the Beijing family. © 2011 Mestre et al.
Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages
(BioMed Central, 2016-02-29) Phelan, Jody E.; Coll, Francesc; Bergval, Indra; Anthony, Richard M.; Warren, Rob; Sampson, Samantha L.; Gey Van Pittius, Nicolaas C.; Glynn, Judith R.; Crampin, Amelia C.; Alves, Adriana; Bessa, Theolis B.; Campino, Susana; Dheda, Keertan; Grandjean, Louis; Hasan, Rumina; Hasan, Zahra; Miranda, Anabela; Moore, David; Panaiotov, Stefan; Perdigao, Joao; Portugal, Isabel; Sheen, Patricia; De Oliveira Sousa, Erivelton; Streicher, Elizabeth M.; Van Helden, Paul D.; Viveiros, Miguel; Hibberd, Martin L.; Pain, Arnab; McNerney, Ruth; Clark, Taane G.
Background: Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results: To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions: This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.

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