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Garcia De Viedma D.,Hospital General Universitario Gregorio Maranon | Garcia De Viedma D.,CIBER ISCIII | Mokrousov I.,St Petersburg Pasteur Institute | Rastogi N.,Institute Pasteur Of Guadeloupe Morne Joliviere
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2011

The application of genotyping tools to the analysis of tuberculosis (TB) has allowed us to identify clinical isolates of Mycobacterium tuberculosis to strain level. M. tuberculosis fingerprinting has been applied at different levels: a) in the laboratory, to optimize identification of cross-contamination events which can lead to a false diagnosis; b) in the patient, to determine whether recurrences are due to reactivations or exogenous reinfections or to identify cases coinfected by more than one strain; c) at the micropopulation level, to identify clusters of cases infected by the same strains (recent transmission) and to differentiate them from orphan cases that are most probably due to reactivations; and d) at the macropopulation level, to define the global distribution of M. tuberculosis lineages, to monitor the international spread of high-risk strains, and to explore the evolutionary features of M. tuberculosis. In recent years, important methodological and strategic advances have been applied at these different levels of analysis. Rather than provide an exhaustive review, the present study focuses on specific advances in micropopulation and macropopulation analysis. © 2011 Elsevier España S.L. Source


Valcheva V.,Bulgarian Academy of Science | Mokrousov I.,St Petersburg Pasteur Institute
Biotechnology and Biotechnological Equipment | Year: 2011

Emergence of multidrug-resistant Mycobacterium tuberculosis strains and their global dissemination necessitate development, evaluation and comparison of the rapid molecular tests that target genetic determinants of bacterial drug resistance. A wide range of such methods is available at present and the choice of those most appropriate is among the pertinent tasks of the National Tuberculosis Control Programs. Inadequate and/or interrupted therapy allows the selection of spontaneous mutations in favor of resistant organisms while sequential acquisition of these mutations in different genome loci results in the development of resistance to multiple drugs. The standard DOTS course comprises the five first-line drugs: rifampin (RIF), isoniazid (INH), streptomycin (STR), ethambutol (EMB), and pyrazinamide (PZA). Multi-drug resistance (MDR) is defined as resistance to at least RIF and INH. Anti-TB drug resistance is characterized by multigenic (rpoB, katG, inhA, ndh, embB, rpsL, rrs, pncA, gyrA) control and geographic variation of resistance mutations. Correct and rapid detection of drug resistance facilitates the appropriate and timely delivery of anti-TB therapy and reduces overall treatment cost. The prediction of drug resistance of M. tuberculosis by molecular tools presents a rapid alternative to the culture-based phenotypic susceptibility tests. Among the genotypic methods used to date are direct sequencing, microchips technology, PCR-single strand conformation polymorphism, RNA/RNA mismatch, molecular beacons and other assays. Genotypic methods allow rapid prediction of resistance to main anti- TB drugs in the considerable proportion of M. tuberculosis strains circulating in areas with high burden of MDR-TB. Source


Ogarkov O.,Research Institute of Epidemiology and Microbiology | Mokrousov I.,St Petersburg Pasteur Institute | Sinkov V.,Irkutsk Regional Diagnostic Center | Zhdanova S.,Research Institute of Epidemiology and Microbiology | And 2 more authors.
Infection, Genetics and Evolution | Year: 2012

An interaction of different human alleles and endemic bacterial strains may be clinically manifested as different outcome of the disease in different hosts infected with the same genotype. The primary objective of this study was to investigate this issue in the model of Mycobacterium tuberculosis and human DC-SIGN encoding CD209 promoter SNP (rs4804803) in Russian Siberian population. We sought to find a possible combination of M. tuberculosis lineage and human host allele/genotype correlating with unfavorable outcome of the disease. The 101 paired DNA samples from patients with pulmonary TB (human and M. tuberculosis DNA) were studied by 12-loci MIRU-VNTR typing (M. tuberculosis strains) and CD209 -336 A/G typing (human DNA). Ninety autopsy DNA samples as a source of human and mycobacterial nucleic acids from persons who died from TB were also subjected to the same genotyping procedures. A human control group consisted of 177 healthy individuals. The Beijing genotype was more frequently identified in autopsy versus patient samples, in 70.0% and 51.5%, respectively (χ 2=6.06, P=0.01). Regarding other M. tuberculosis genetic families, no significant difference in LAM family distribution among patient strains and autopsy samples has been found. In contrast, Ural genotype was significantly less frequently detected in the autopsy samples (χ 2=6.12, P=0.01). Allelic and genotypic frequencies of the CD209 -336A/G did not differ significantly under global comparison when contrasting controls versus patients versus autopsy samples. However intriguing and contrasting significant associations were found in the male subgroup under M. tuberculosis genotype-stratified comparisons. Firstly, male carriers of -336AA genotype were more frequently infected with Beijing genotype (χ 2=5.2, P=0.02). Secondly and remarkably, this association was inverted in the autopsy sample: male carriers of -336AA genotype died less frequently due to TB caused by a Beijing rather than a non-Beijing strain (χ 2=5.37, P=0.02). In conclusion, we hypothesize that although carriers of CD209 -336A allele are more sensitive to infection with a Beijing strain, a combination of human CD209 -336G allele and M. tuberculosis Beijing genotype leads more frequently to the lethal outcome in pulmonary TB male patients in Russian (Caucasian) population. © 2011 Elsevier B.V.. Source


Demay C.,Institute Pasteur Of Guadeloupe | Liens B.,Institute Pasteur Of Guadeloupe | Burguiere T.,Institute Pasteur Of Guadeloupe | Hill V.,Institute Pasteur Of Guadeloupe | And 6 more authors.
Infection, Genetics and Evolution | Year: 2012

Among various genotyping methods to study Mycobacterium tuberculosis complex (MTC) genotypic polymorphism, spoligotyping and mycobacterial interspersed repetitive units-variable number of DNA tandem repeats (MIRU-VNTRs) have recently gained international approval as robust, fast, and reproducible typing methods generating data in a portable format. Spoligotyping constituted the backbone of a publicly available database SpolDB4 released in 2006; nonetheless this method possesses a low discriminatory power when used alone and should be ideally used in conjunction with a second typing method such as MIRU-VNTRs for high-resolution epidemiological studies. We hereby describe a publicly available international database named SITVITWEB which incorporates such multimarker data allowing to have a global vision of MTC genetic diversity worldwide based on 62,582 clinical isolates corresponding to 153 countries of patient origin (105 countries of isolation). We report a total of 7105 spoligotype patterns (corresponding to 58,180 clinical isolates) - grouped into 2740 shared-types or spoligotype international types (SIT) containing 53,816 clinical isolates and 4364 orphan patterns. Interestingly, only 7% of the MTC isolates worldwide were orphans whereas more than half of SITed isolates (n=27,059) were restricted to only 24 most prevalent SITs. The database also contains a total of 2379 MIRU patterns (from 8161 clinical isolates) from 87 countries of patient origin (35 countries of isolation); these were grouped in 847 shared-types or MIRU international types (MIT) containing 6626 isolates and 1533 orphan patterns. Lastly, data on 5-locus exact tandem repeats (ETRs) were available on 4626 isolates from 59 countries of patient origin (22 countries of isolation); a total of 458 different VNTR patterns were observed - split into 245 shared-types or VNTR International Types (VIT) containing 4413 isolates) and 213 orphan patterns. Datamining of SITVITWEB further allowed to update rules defining MTC genotypic lineages as well to have a new insight into MTC population structure and worldwide distribution at country, sub-regional and continental levels. At evolutionary level, the data compiled may be useful to distinguish the occasional convergent evolution of genotypes versus specific evolution of sublineages essentially influenced by adaptation to the host. This database is publicly available at: http://www.pasteur-guadeloupe.fr:8081/SITVIT_ONLINE. © 2012 Elsevier B.V.. Source


Mokrousov I.,St Petersburg Pasteur Institute
Infection, Genetics and Evolution | Year: 2012

The absence of lateral gene exchange is a characteristic feature defining the genome evolution and clonal population structure of Mycobacterium tuberculosis. Certain of its lineages have justly attracted more attention due to their global dissemination and/or remarkable pathogenic properties. In this critical review, I discuss the population structure and genetic geography of the less 'popular' but in some aspects no less noteworthy M. tuberculosis lineage, Ural family. Its specific signature was initially defined by single copy in MIRU26, and large (>6) copy number in MIRU10 loci, and by 43-spoligotyping as absence of signals 29-31 and 33-36. Here, I suggest to subdivide Ural strains with present and absent spoligosignal 2 into primary Ural-1 and secondary Ural-2 sublineages, respectively, while 1 copy in MIRU26 is specific of Ural-1. Furthermore, three copies were recently described in MIRU10 in Ural-1 strains which highlights a high diversity of this locus in Ural genotype. The data on the two Ural sublineages were extracted from SpolDB4 database and original publications in order to trace their distribution at global and within-country levels. Importantly, the rigorous reanalysis suggested the true rate of the Ural genotype in the Ural area in Russia to be only 7%. In contrast, the frequencies of the Ural sublineages peak elsewhere: in South Ukraine and Georgia/Abkhazia (Ural-1, up to 14-19%), and in southwestern Iran (Ural-2, up to 26%). However, as this name is used since 2005, it seems most parsimonious to continue its use even if misleading. The forest graph was built on the available spoligoprofiles of Ural family strains from Eurasia. It helped to suggest routes of their primary dispersal that are discussed in the context of the known human migrations also influenced by natural barriers. The north/east Pontic area may have been an area of origin and primary dispersal of the Ural (Ural-1) genotype in Eurasia, whereas political and natural borders may have influenced its subsequent dissemination throughout Central Asia. Studies of phenotypic properties in different models, comparison with host genetics give evidence that the Ural family strains are not associated with increased capacity to acquire drug resistance, pathogenicity or transmissibility. Instead since Ural family is rather moderately widespread in Eurasia beyond the hypothesized areas of origin, this situation may be a result of its low contagiosity as a consequence of long-term co-adaptation with human host. Future research should be focused on whole-genome sequencing in order to identify Ural-specific SNP and/or deletion, to resolve its phylogenetic and phylogeographic uncertainty and to elucidate biological features underlying its circulation and co-evolution with the human species. © 2011 Elsevier B.V.. Source

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