Browsing by Author "Muller, Borna"
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- ItemComparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and apparent absence of selective constraints(Public Library of Science, 2012-04-04) McEvoy, Christopher R. E.; Cloete, Ruben; Muller, Borna; Schurch, Anita C.; Van Helden, Paul D.; Gagneux, Sebastien; Warren, Robin M.; Gey van Pittius, Nicolaas C.Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of “classical” antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design.
- ItemDifferences in primary sites of infection between zoonotic and human tuberculosis : results from a worldwide systematic review(Public Library of Science, 2013-08-29) Durr, Salome; Muller, Borna; Alonso, Silvia; Hattendorf, Jan; Laisse, Claudio J. M.; Van Helden, Paul D.; Zinsstag, JakobTuberculosis (TB) is one of the most devastating infectious diseases worldwide. Whilst global burden estimates for M. tuberculosis infection (MtTB) are well established, accurate data on the contribution of zoonotic TB (zTB) caused by M. bovis or M. caprae to human TB are scarce. The association of M. bovis infection with extrapulmonary tuberculosis has been suggested repeatedly, though there is little scientific evidence available to support this relationship. The present study aimed to determine globally the occurrence of extrapulmonary TB and the primary site (i.e. primary body location affected) of zTB in comparison with MtTB, based on previously published reports. A systematic literature review was conducted in 32 different bibliographic databases, selecting reports on zTB written in English, French, German, Spanish or Portuguese. Data from 27 reports from Africa, America, Europe and the Western Pacific Region were extracted for analyses. Low income countries, in Africa and South-East Asia, were highly underrepresented in the dataset. The median proportion of extrapulmonary TB cases was significantly increased among zTB in comparison with data from registries of Europe and USA, reporting mainly MtTB cases (47% versus 22% in Europe, 73% versus 30% in the USA). These findings were confirmed by analyses of eight studies reporting on the proportions of extrapulmonary TB in comparable populations of zTB and MtTB cases (median 63% versus 22%). Also, disparities of primary sites of extrapulmonary TB between zTB and MtTB were detected. Our findings, based on global data, confirm the widely suggested association between zTB and extrapulmonary disease. Different disability weights for zTB and MtTB should be considered and we recommend separate burden estimates for the two diseases.
- ItemZoonotic Mycobacterium bovis : induced tuberculosis in humans(Centers for Disease Control and Prevention, 2013-06) Muller, Borna; Durr, Salome; Alonso, Silvia; Hattendorf, Jan; Laisse, Claudio J. M.; Parsons, Sven D. C.; Van Helden, Paul D.; Zinsstag, JakobWe aimed to estimate the global occurrence of zoonotic tuberculosis (TB) caused by Mycobacterium bovis or M. caprae infections in humans by performing a multilingual, systematic review and analysis of relevant scientific literature of the last 2 decades. Although information from many parts of the world was not available, data from 61 countries suggested a low global disease incidence. In regions outside Africa included in this study, overall median proportions of zoonotic TB of ≤1.4% in connection with overall TB incidence rates ≤71/100,000 population/year suggested low incidence rates. For countries of Africa included in the study, we multiplied the observed median proportion of zoonotic TB cases of 2.8% with the continental average overall TB incidence rate of 264/100,000 population/year, which resulted in a crude estimate of 7 zoonotic TB cases/100,000 population/year. These generally low incidence rates notwithstanding, available data indicated substantial consequences of this disease for some population groups and settings.