virulence; evolution; HIV; mixed infection; drug resistance; microbiology; mycobacteria; patient outcome; molecular epidemiology
Coscolla Mireia, Gagneux Sebastien, Menardo Fabrizio, Loiseau Chloé, Ruiz-Rodriguez Paula, Borrell Sonia, Otchere Isaac Darko, Asante-Poku Adwoa, Asare Prince, Sánchez-Busó Leonor, Gehre Florian, Sanoussi C. N’Dira, Antonio Martin, Affolabi Dissou, Fyfe Janet, Beckert Patrick, Niemann Stefan, Alabi Abraham S., Grobusch Martin P., Kobbe Robin, Parkhill Julian, Beisel Christian, Fenner Lukas, Böttger Erik C., et al. (2021), Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history, in Microbial Genomics
Menardo Fabrizio, Gagneux Sébastien, Freund Fabian (2021), Multiple Merger Genealogies in Outbreaks of Mycobacterium tuberculosis, in Molecular Biology and Evolution
, 38(1), 290-306.
Castro Rhastin A D, Borrell Sonia, Gagneux Sebastien (2020), The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis, in FEMS Microbiology Reviews
Ngabonziza Jean Claude Semuto, Loiseau Chloé, Marceau Michael, Jouet Agathe, Menardo Fabrizio, Tzfadia Oren, Antoine Rudy, Niyigena Esdras Belamo, Mulders Wim, Fissette Kristina, Diels Maren, Gaudin Cyril, Duthoy Stéphanie, Ssengooba Willy, André Emmanuel, Kaswa Michel K., Habimana Yves Mucyo, Brites Daniela, Affolabi Dissou, Mazarati Jean Baptiste, de Jong Bouke Catherine, Rigouts Leen, Gagneux Sebastien, Meehan Conor Joseph, et al. (2020), A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region, in Nature Communications
, 11(1), 2917-2917.
Reichmuth Martina L., Hömke Rico, Zürcher Kathrin, Sander Peter, Avihingsanon Anchalee, Collantes Jimena, Loiseau Chloé, Borrell Sonia, Reinhard Miriam, Wilkinson Robert J., Yotebieng Marcel, Fenner Lukas, Böttger Erik C., Gagneux Sebastien, Egger Matthias, Keller Peter M. (2020), Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients, in Antimicrobial Agents and Chemotherapy
, 64(11), e00513-20.
Loiseau Chloé, Brites Daniela, Reinhard Miriam, Zürcher Kathrin, Borrell Sonia, Ballif Marie, Fenner Lukas, Cox Helen, Rutaihwa Liliana K., Wilkinson Robert J., Yotebieng Marcel, Carter E. Jane, Abimiku Alash'le, Marcy Olivier, Gotuzzo Eduardo, Avihingsanon Anchalee, Zetola Nicola, Doulla Basra, Böttger Erik C., Egger Matthias, Gagneux Sebastien (2020), HIV Coinfection Is Associated with Low-Fitness rpoB Variants in Rifampicin-Resistant Mycobacterium tuberculosis, in Antimicrobial Agents and Chemotherapy
, 64(10), e00782-20.
Øyås Ove, Borrell Sonia, Trauner Andrej, Zimmermann Michael, Feldmann Julia, Liphardt Thomas, Gagneux Sebastien, Stelling Jörg, Sauer Uwe, Zampieri Mattia (2020), Model-based integration of genomics and metabolomics reveals SNP functionality in Mycobacterium tuberculosis, in Proceedings of the National Academy of Sciences
, 117(15), 8494-8502.
Loiseau Chloé, Menardo Fabrizio, Aseffa Abraham, Hailu Elena, Gumi Balako, Ameni Gobena, Berg Stefan, Rigouts Leen, Robbe-Austerman Suelee, Zinsstag Jakob, Gagneux Sebastien, Brites Daniela (2020), An African origin for Mycobacterium bovis, in Evolution, Medicine, and Public Health
, 2020(1), 49-59.
Castro Rhastin A D, Ross Amanda, Kamwela Lujeko, Reinhard Miriam, Loiseau Chloé, Feldmann Julia, Borrell Sonia, Trauner Andrej, Gagneux Sebastien (2020), The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis, in Molecular Biology and Evolution
, 37(1), 195-207.
Maghradze Nino, Jugheli Levan, Borrell Sonia, Tukvadze Nestani, Aspindzelashvili Rusudan, Avaliani Zaza, Reither Klaus, Gagneux Sebastien (2019), Classifying recurrent Mycobacterium tuberculosis cases in Georgia using MIRU-VNTR typing, in PLOS ONE
, 14(10), e0223610-e0223610.
Castro Rhastin A D, Ross Amanda, Kamwela Lujeko, Reinhard Miriam, Loiseau Chloé, Feldmann Julia, Borrell Sonia, Trauner Andrej, Gagneux Sebastien (2019), The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis, in Molecular Biology and Evolution
Menardo Fabrizio, Duchêne Sebastian, Brites Daniela, Gagneux Sebastien (2019), The molecular clock of Mycobacterium tuberculosis, in PLOS Pathogens
, 15(9), e1008067-e1008067.
Loiseau Chloé, Brites Daniela, Moser Irmgard, Coll Francesc, Pourcel Christine, Robbe-Austerman Suelee, Escuyer Vincent, Musser Kimberlee A., Peacock Sharon J., Feuerriegel Silke, Kohl Thomas A., Niemann Stefan, Gagneux Sebastien, Köser Claudio U. (2019), Revised Interpretation of the Hain Lifescience GenoType MTBC To Differentiate Mycobacterium canettii and Members of the Mycobacterium tuberculosis Complex, in Antimicrobial Agents and Chemotherapy
, 63(6), e00159.
Payne Joshua L., Menardo Fabrizio, Trauner Andrej, Borrell Sonia, Gygli Sebastian M., Loiseau Chloe, Gagneux Sebastien, Hall Alex R. (2019), Transition bias influences the evolution of antibiotic resistance in Mycobacterium tuberculosis, in PLOS Biology
, 17(5), e3000265-e3000265.
Gygli Sebastian M., Keller Peter M., Ballif Marie, Blöchliger Nicolas, Hömke Rico, Reinhard Miriam, Loiseau Chloé, Ritter Claudia, Sander Peter, Borrell Sonia, Collantes Loo Jimena, Avihingsanon Anchalee, Gnokoro Joachim, Yotebieng Marcel, Egger Matthias, Gagneux Sebastien, Böttger Erik C. (2019), Whole-Genome Sequencing for Drug Resistance Profile Prediction in Mycobacterium tuberculosis, in Antimicrobial Agents and Chemotherapy
, 63(4), e02175.
Rutaihwa Liliana K., Sasamalo Mohamed, Jaleco Aladino, Hella Jerry, Kingazi Ally, Kamwela Lujeko, Kingalu Amri, Malewo Bryceson, Shirima Raymond, Doetsch Anna, Feldmann Julia, Reinhard Miriam, Borrell Sonia, Brites Daniela, Reither Klaus, Doulla Basra, Fenner Lukas, Gagneux Sebastien (2019), Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania, in PLOS ONE
, 14(4), e0206334-e0206334.
Borrell Sònia, Trauner Andrej, Brites Daniela, Rigouts Leen, Loiseau Chloe, Coscolla Mireia, Niemann Stefan, De Jong Bouke, Yeboah-Manu Dorothy, Kato-Maeda Midori, Feldmann Julia, Reinhard Miriam, Beisel Christian, Gagneux Sebastien (2019), Reference set of Mycobacterium tuberculosis clinical strains: A tool for research and product development, in PLOS ONE
, 14(3), e0214088-e0214088.
Otchere Isaac Darko, Coscollá Mireia, Sánchez-Busó Leonor, Asante-Poku Adwoa, Brites Daniela, Loiseau Chloe, Meehan Conor, Osei-Wusu Stephen, Forson Audrey, Laryea Clement, Yahayah Abdallah Iddrisu, Baddoo Akosua, Ansa Gloria Akosua, Aboagye Samuel Yaw, Asare Prince, Borrell Sonia, Gehre Florian, Beckert Patrick, Kohl Thomas A., N’dira Sanoussi, Beisel Christian, Antonio Martin, Niemann Stefan, de Jong Bouke C., et al. (2018), Comparative genomics of Mycobacterium africanum Lineage 5 and Lineage 6 from Ghana suggests distinct ecological niches, in Scientific Reports
, 8(1), 11269-11269.
Menardo Fabrizio, Loiseau Chloé, Brites Daniela, Coscolla Mireia, Gygli Sebastian M., Rutaihwa Liliana K., Trauner Andrej, Beisel Christian, Borrell Sonia, Gagneux Sebastien (2018), Treemmer: a tool to reduce large phylogenetic datasets with minimal loss of diversity, in BMC Bioinformatics
, 19(1), 164-164.
Conceição Emilyn Costa, Guimarães Arthur Emil dos Santos, Lopes Maria Luíza, Furlaneto Ismari Perini, Rodrigues Yan Corrêa, da Conceição Marília Lima, Barros Wandyra Araújo, Cardoso Ninarosa Calzavara, Sharma Abhinav, Lima Luana Nepomuceno Gondim Costa, Gomes Harrison Magdinier, Duarte Rafael Silva, Frota Cristiane, Rutaihwa Liliana K., Gagneux Sebastien, Suffys Philip Noel, Lima Karla Valéria Batista (2018), Analysis of potential household transmission events of tuberculosis in the city of Belem, Brazil, in Tuberculosis
, 113, 125-129.
Brites Daniela, Loiseau Chloé, Menardo Fabrizio, Borrell Sonia, Boniotti Maria Beatrice, Warren Robin, Dippenaar Anzaan, Parsons Sven David Charles, Beisel Christian, Behr Marcel A., Fyfe Janet A., Coscolla Mireia, Gagneux Sebastien (2018), A New Phylogenetic Framework for the Animal-Adapted Mycobacterium tuberculosis Complex, in Frontiers in Microbiology
, 9, 2820.
Kühnert Denise, Coscolla Mireia, Brites Daniela, Stucki David, Metcalfe John, Fenner Lukas, Gagneux Sebastien, Stadler Tanja (2018), Tuberculosis outbreak investigation using phylodynamic analysis, in Epidemics
Gagneux Sebastien (2018), Ecology and evolution of Mycobacterium tuberculosis, in Nature Reviews Microbiology
, 16(4), 202-213.
Ghielmetti Giovanni, Coscolla Mireia, Ruetten Maja, Friedel Ute, Loiseau Chloé, Feldmann Julia, Steinmetz Hanspeter W., Stucki David, Gagneux Sebastien (2017), Tuberculosis in Swiss captive Asian elephants: microevolution of Mycobacterium tuberculosis characterized by multilocus variable-number tandem-repeat analysis and whole-genome sequencing, in Scientific Reports
, 7(1), 14647-14647.
Background: Tuberculosis (TB) is a major public health problem globally, and particularly in Brazil, which remains one of the 22 TB high-burden countries defined by the World Health Organization. Pulmonary TB is primarily caused by Mycobacterium tuberculosis (Mtb), but other nontuberculous mycobacteria (NTMs) are increasingly being isolated from such patients. The global TB epidemic is partially driven by co-infection with HIV and worsening due to the emergence of multidrug-resistant and extensively drug-resistant Mtb strains. One of the striking facts about TB is that patients can be re-infected following successful treatment. Hence, prior TB infection does not protect against reinfection. Similarly, and against common believes, TB patients can be infected with multiple Mtb genotypes at the same time. Indeed, studies have been reporting mixed infection in up to 60% of patients depending on TB incidence and study setting, but mathematical models predict that in most cases these figures are underestimates, because of the inherent limitations of the methods used to detect mixed infections. Moreover, little is known on the co-occurrence of Mtb and NTMs in TB patients. Recent advances in sample preparation and DNA sequencing offer an opportunity to explore mixed-strain infections in TB. Because mixed infections in TB have been highly neglected, little empirical data exist with respect to their impact on treatment outcome. Another neglected field in TB research is hetero-resistance, which refers to the co-occurrence of drug-susceptible and drug-resistant Mtb strains in the same individual. Hetero-resistance can emerge de novo during the development of drug resistance in a patient failing anti-TB drug therapy, or through initial co-infection or sequential superinfection of different Mtb strains with varying drug susceptibility profiles. The relative importance of these different phenomena for the evolution of drug-resistant Mtb and the outcome of patient treatment has not been determined. A few studies have reported that HIV co-infected TB patients were more likely to carry multiple Mtb genotypes, but it is unknown if and how this relates to the comparably poor treatment outcome of TB/HIV co-infected patients. More generally, little is known on the impact of HIV co-infection on the evolution of drug-susceptible and drug-resistant Mtb. To address these knowledge gaps, we will study TB patients in Rio de Janeiro and apply state-of-the art genotyping and whole genome sequencing (WGS) of Mtb isolates directly from sputum samples.Goal, Hypotheses and Objectives: The overall goal of this project is to study the biology and epidemiology of mixed infections with different strains of Mtb and/or NTMs and hetero-resistance in patients who start anti-TB treatment and the association with treatment outcome. We hypothesise that i) mixed infections (as defined above) and hetero-resistance occur more often in TB patients suffering from treatment failure, ii) mixed infection and hetero-resistance occur more often in patients co-infected with HIV, and iii) mixed infection and hetero-resistance occur more often in patients with previous TB treatment and/or drug-resistant TB. We will test these hypotheses by addressing the following Objectives:1.To study the nature and frequency of mixed infections and hetero-resistance in TB patients from Rio de Janeiro;2.To analyse the association of mixed infections and hetero-resistance with epidemiological and laboratory variables;3.To link mixed infections and/or hetero-resistance to treatment failure in TB patients;4.To investigate the nature and frequency of mixed infections and hetero-resistance as a function of HIV co-infection and anti-TB drug resistance.Study Setting, General Approach, and Methods: This project is embedded in a larger study funded by the National Institutes of Health and the Departamento Ciência Tecnologia - Secretaria de Ciência Tecnologia do Ministério da Saúde, on which the Brazilian Principal Investigator of this proposal (Prof. Kritski) is a Co-Principal Investigator. This larger study focuses on the immunology of progression from latent to active TB. The proposed project will take advantage of the available infrastructure and resources to recruit TB patients at four TB clinics in Rio de Janeiro during a period of 18 months. A total of 780 culture-positive TB patients will be recruited and their sputum samples subjected to standard genotyping to detect signals of mixed infection by different Mtb and/or NTM strains. Based on our preliminary data, we anticipate that a minimum of 10-20% of patients will harbour more than one mycobacterial strain, depending on HIV-status and drug resistance profile. All patient samples showing evidence of mixed infection will be subjected to WGS performed directly on sputum to avoid any potential bias introduced during the culturing step. As a back-up, WGS will be performed on multiple colonies obtained from bacterial cultures. Because TB patients with HIV co-infection and/or drug resistance will be comparably few, these will all be subjected to WGS analysis, irrespective of whether they show evidence of mixed infection based on standard Mtb genotyping. Moreover, to study hetero-resistance in detail and differentiate intra-host evolution from mixed or superinfection, we will clone individual PCR products obtained from sputum samples and directly sequence. This will allow us to reconstruct the specific haplotypes in mixed bacterial populations, which currently cannot easily be inferred from Illumine sequencing data alone. We will combine these Mtb genetic data to detailed clinical and epidemiological data obtained through our ongoing cohort study and look for associations between mixed strain infections and patient variables, including culture conversion at 2 months and treatment outcome at 6 months post treatment initiation. We will use a nested case-control study to compare TB patients with and without mixed infections and identify risk factors and patient characteristics associated with mixed infections. Moreover, we will use the WGS data to study the intra-host evolution of Mtb as a function of HIV co-infection and anti-TB drug resistance.Significance: This project will generate for the first time detailed data on the nature and frequency of mixed-strain infections in TB patients from Brazil as well as its impact on patient treatment outcome. Moreover, we will define risk factors and other patient variables associated with mixed infections. Because we will be able to combine the data generated in this project with data from the larger immunological study, this project will also shed new light on the impact of mixed-strain infections on the immune response to TB infection, and inform the development of new TB vaccines and biomarkers. Finally, our project will explore the diversity of Mtb in individual patients during treatment and generate new knowledge on the evolution of Mtb in the context of HIV co-infection and drug-resistant TB, as well as contribute to a better understanding of the role of hetero-resistance in the emergence of anti-TB drug resistance and its impact on treatment outcome.