RECONNECTING TRANSMISSION TO GLOBAL TUBERCULOSIS CONTROL BY MAPPING PATHOGEN TRANSMISSION EVENTS TO HOST INFECTION STATUS

Grant agreement ID: 101001038
Ongoing project: 1 July 2021 – 30 June 2026
Funding: 2,723,027.00 €

The project

TB-RECONNECT IS an ERC project at IBV-CSIC with PI Iñaki Comas.

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement ID 101001038.


Tuberculosis (TB) control programmes’ slow progress in reducing TB incidence has many causes, including lapses in the TB care cascade and insufficient incorporation of new knowledge about transmission in control efforts. There is growing consensus that asymptomatic individuals with active TB are likely to transmit the disease. The EU-funded TB-RECONNECT project will address the nature of TB transmission in connection with the host and pathogen biology to improve global and local control strategies. Research developments will include host blood transcriptomics analysis of infection status within the latent pool of individuals. Pathogen genome sequencing will enable high-resolution transmission quantification and epidemiological modelling to identify transmission timing and impact on global TB control.

Objective

The annual decline in tuberculosis (TB) incidence is not greatly different from that of the ‘90s, when no coordinated efforts in global tuberculosis control were in place. The failure of current TB control programmes to accelerate TB elimination has multiple causes, including losses of TB cases at the different steps of the TB care cascade, and a chronic lack of funding hampering innovation. Additionally, we have failed to halt transmission in many settings, as we have failed to incorporate our improved understanding of transmission in TB control programmes. Our current approach to controlling TB is focused on a narrow view of who is transmitting the disease (symptomatically active TB cases), while there is a growing consensus that the traditional latent/active dichotomy is no longer valid, and that asymptomatic individuals with active TB signatures are also likely to be transmitting the disease. There is a critical lack of high-resolution data from different settings on the contribution to the transmission burden of cases with different infection statuses. To fill this evidence gap, I propose synergizing three recent TB research developments; We can now use host blood transcriptomics to discriminate between infection status within the latent pool of individuals. We can now quantify transmission at a resolution not previously available, using pathogen genome sequencing. We can now use phylogenetic and epidemiological models to identify when transmission has happened. Combining these three key developments with TB cohorts from multiple settings, and available tools from bacterial population genetics, high-throughput functional genomics and infection biology, we will be in a key position to answer these burning questions about the nature of TB transmission and the host and pathogen biology behind this. More importantly, we will reconnect transmission to TB control, to inform major shifts in global and local control strategies.

Published results

  • 1: García-Marín AM, Cancino-Muñoz I, Torres-Puente M, Villamayor LM, Borrás R, Borrás-Máñez M, Bosque M, Camarena JJ, Colomer-Roig E, Colomina J, Escribano I, Esparcia-Rodríguez O, Gil-Brusola A, Gimeno C, Gimeno-Gascón A, Gomila-Sard B, González-Granda D, Gonzalo-Jiménez N, Guna-Serrano MR, López-Hontangas JL, Martín-González C, Moreno-Muñoz R, Navarro D, Navarro M, Orta N, Pérez E, Prat J, Rodríguez JC, Ruiz-García MM, Vanaclocha H; Valencia Region Tuberculosis Working Group; González-Candelas F, Furió V, Comas I. Role of the first WHO mutation catalogue in the diagnosis of antibiotic resistance in Mycobacterium tuberculosis in the Valencia Region, Spain: a retrospective genomic analysis. Lancet Microbe. 2024 Jan;5(1):e43-e51. doi: 10.1016/S2666-5247(23)00252-5. Epub 2023 Dec 4. PMID: 38061383; PMCID: PMC10790317.
  • 2: Mariner-Llicer C, Saavedra Cervera B, Mambuque E, Gomes N, Munguambe S, Villamayor L, Cancino-Muñoz I, Torres-Puente M, Nguenha D, Respeito D, Tembe G, López MG, Comas I, García-Basteiro AL. Monitoring of First-line Drug Resistance Mutations Outside the Scope of Xpert MTB/RIF Ultra is Needed for Successful Control of DR-TB in Southern Mozambique. Clin Infect Dis. 2023 Dec 4:ciad684. doi: 10.1093/cid/ciad684. Epub ahead of print. PMID: 38048599.
  • 3: Martínez-Martínez FJ, Massinga AJ, De Jesus Á, Ernesto RM, Cano-Jiménez P, Chiner-Oms Á, Gómez-Navarro I, Guillot-Fernández M, Guinovart C, Sitoe A, Vubil D, Bila R, Gujamo R, Enosse S, Jiménez-Serrano S, Torres-Puente M, Comas I, Mandomando I, López MG, Mayor A. Tracking SARS-CoV-2 introductions in Mozambique using pandemic-scale phylogenies: a retrospective observational study. Lancet Glob Health. 2023 Jun;11(6):e933-e941. doi: 10.1016/S2214-109X(23)00169-9. PMID: 37202028; PMCID: PMC10187989.
  • 4: Hailu E, Cantillon D, Madrazo C, Rose G, Wheeler PR, Golby P, Adnew B, Gagneux S, Aseffa A, Gordon SV, Comas I, Young DB, Waddell SJ, Larrouy-Maumus G, Berg S. Lack of methoxy-mycolates characterizes the geographically restricted lineage 7 of Mycobacterium tuberculosis complex. Microb Genom. 2023 May;9(5):mgen001011. doi: 10.1099/mgen.0.001011. PMID: 37171244; PMCID: PMC10272862.
  • 5: López MG, Campos-Herrero MI, Torres-Puente M, Cañas F, Comín J, Copado R, Wintringer P, Iqbal Z, Lagarejos E, Moreno-Molina M, Pérez-Lago L, Pino B, Sante L, García de Viedma D, Samper S, Comas I. Deciphering the Tangible Spatio- Temporal Spread of a 25-Year Tuberculosis Outbreak Boosted by Social Determinants. Microbiol Spectr. 2023 Feb 14;11(2):e0282622. doi: 10.1128/spectrum.02826-22. Epub ahead of print. PMID: 36786614; PMCID: PMC10100973.
  • 6: Comas I, Moreno-Molina M. Phenogenomics of Mycobacterium abscessus. Nat Microbiol. 2022 Sep;7(9):1325-1326. doi: 10.1038/s41564-022-01217-6. PMID: 36008618.
  • 7: Cancino-Muñoz I, López MG, Torres-Puente M, Villamayor LM, Borrás R, Borrás- Máñez M, Bosque M, Camarena JJ, Colijn C, Colomer-Roig E, Colomina J, Escribano I, Esparcia-Rodríguez O, García-García F, Gil-Brusola A, Gimeno C, Gimeno-Gascón A, Gomila-Sard B, Gónzales-Granda D, Gonzalo-Jiménez N, Guna-Serrano MR, López- Hontangas JL, Martín-González C, Moreno-Muñoz R, Navarro D, Navarro M, Orta N, Pérez E, Prat J, Rodríguez JC, Ruiz-García MM, Vanaclocha H; Valencia Region Tuberculosis Working Group; Comas I. Population-based sequencing of Mycobacterium tuberculosis reveals how current population dynamics are shaped by past epidemics. Elife. 2022 Jul 26;11:e76605. doi: 10.7554/eLife.76605. PMID: 35880398; PMCID: PMC9323001.
  • 8: Ginex T, Marco-Marín C, Wieczór M, Mata CP, Krieger J, Ruiz-Rodriguez P, López-Redondo ML, Francés-Gómez C, Melero R, Sánchez-Sorzano CÓ, Martínez M, Gougeard N, Forcada-Nadal A, Zamora-Caballero S, Gozalbo-Rovira R, Sanz-Frasquet C, Arranz R, Bravo J, Rubio V, Marina A; IBV-Covid19-Pipeline; Geller R, Comas I, Gil C, Coscolla M, Orozco M, Llácer JL, Carazo JM. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation. PLoS Pathog. 2022 Jul 11;18(7):e1010631. doi: 10.1371/journal.ppat.1010631. Erratum in: PLoS Pathog. 2022 Nov 23;18(11):e1010995. PMID: 35816514; PMCID: PMC9302720.
  • 9: Saavedra Cervera B, López MG, Chiner-Oms Á, García AM, Cancino-Muñoz I, Torres-Puente M, Villamayor L, Madrazo-Moya C, Mambuque E, Sequera GV, Respeito D, Blanco S, Augusto O, López-Varela E, García-Basteiro AL, Comas I. Fine-grain population structure and transmission patterns of Mycobacterium tuberculosis in southern Mozambique, a high TB/HIV burden area. Microb Genom. 2022 Jul;8(7):mgen000844. doi: 10.1099/mgen.0.000844. PMID: 35787782; PMCID: PMC9455694.
  • 10: Chiner-Oms Á, López MG, Moreno-Molina M, Furió V, Comas I. Gene evolutionary trajectories in Mycobacterium tuberculosis reveal temporal signs of selection. Proc Natl Acad Sci U S A. 2022 Apr 26;119(17):e2113600119. doi: 10.1073/pnas.2113600119. Epub 2022 Apr 22. Erratum in: Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2208725119. PMID: 35452305; PMCID: PMC9173582.
  • 11: Antimycobacterial Susceptibility Testing Group. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment. Eur Respir J. 2022 Apr 14;59(4):2200166. doi: 10.1183/13993003.00166-2022. PMID: 35422426; PMCID: PMC9059840.
  • 12: Pérez-Cataluña A, Chiner-Oms Á, Cuevas-Ferrando E, Díaz-Reolid A, Falcó I, Randazzo W, Girón-Guzmán I, Allende A, Bracho MA, Comas I, Sánchez G. Spatial and temporal distribution of SARS-CoV-2 diversity circulating in wastewater. Water Res. 2022 Mar 1;211:118007. doi: 10.1016/j.watres.2021.118007. Epub 2021 Dec 24. PMID: 35033744; PMCID: PMC8702378.
  • 13: Mariner-Llicer C, Goig GA, Zaragoza-Infante L, Torres-Puente M, Villamayor L, Navarro D, Borras R, Chiner-Oms Á, Comas I. Accuracy of an amplicon- sequencing nanopore approach to identify variants in tuberculosis drug- resistance-associated genes. Microb Genom. 2021 Dec;7(12):000740. doi: 10.1099/mgen.0.000740. PMID: 34919513; PMCID: PMC8767343.
  • 14: Furió V, Moreno-Molina M, Chiner-Oms Á, Villamayor LM, Torres-Puente M, Comas I. An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis. Commun Biol. 2021 Nov 24;4(1):1322. doi: 10.1038/s42003-021-02846-z. PMID: 34819627; PMCID: PMC8613195.
  • 15: Ruiz-Rodriguez P, Francés-Gómez C, Chiner-Oms Á, López MG, Jiménez-Serrano S, Cancino-Muñoz I, Ruiz-Hueso P, Torres-Puente M, Bracho MA, D’Auria G, Martinez-Priego L, Guerreiro M, Montero-Alonso M, Gómez MD, Piñana JL; SeqCOVID- SPAIN Consortium; González-Candelas F, Comas I, Marina A, Geller R, Coscolla M. Evolutionary and Phenotypic Characterization of Two Spike Mutations in European Lineage 20E of SARS-CoV-2. mBio. 2021 Dec 21;12(6):e0231521. doi: 10.1128/mBio.02315-21. Epub 2021 Nov 16. PMID: 34781748; PMCID: PMC8593680.
  • 16: López MG, Chiner-Oms Á, García de Viedma D, Ruiz-Rodriguez P, Bracho MA, Cancino-Muñoz I, D’Auria G, de Marco G, García-González N, Goig GA, Gómez- Navarro I, Jiménez-Serrano S, Martinez-Priego L, Ruiz-Hueso P, Ruiz-Roldán L, Torres-Puente M, Alberola J, Albert E, Aranzamendi Zaldumbide M, Bea-Escudero MP, Boga JA, Bordoy AE, Canut-Blasco A, Carvajal A, Cilla Eguiluz G, Cordón Rodríguez ML, Costa-Alcalde JJ, de Toro M, de Toro Peinado I, Del Pozo JL, Duchêne S, Fernández-Pinero J, Fuster Escrivá B, Gimeno Cardona C, González Galán V, Gonzalo Jiménez N, Hernáez Crespo S, Herranz M, Lepe JA, López-Causapé C, López-Hontangas JL, Martín V, Martró E, Milagro Beamonte A, Montes Ros M, Moreno-Muñoz R, Navarro D, Navarro-Marí JM, Not A, Oliver A, Palop-Borrás B, Parra Grande M, Pedrosa-Corral I, Pérez González MC, Pérez-Lago L, Pérez-Ruiz M, Piñeiro Vázquez L, Rabella N, Rezusta A, Robles Fonseca L, Rodríguez-Villodres Á, Sanbonmatsu-Gámez S, Sicilia J, Soriano A, Tirado Balaguer MD, Torres I, Tristancho A, Marimón JM; SeqCOVID-Spain consortium; Coscolla M, González- Candelas F, Comas I. The first wave of the COVID-19 epidemic in Spain was associated with early introductions and fast spread of a dominating genetic variant. Nat Genet. 2021 Oct;53(10):1405-1414. doi: 10.1038/s41588-021-00936-6. Epub 2021 Sep 30. PMID: 34594042; PMCID: PMC8481935.

Thesis

  • Advancing molecular tools in tuberculosis control in a high TB/HIV burden area: evaluation of new diagnostics and application of genomic analysis
    • Author: Belén Saavedra Cervera
    • Supervision: Alberto L. García Basteiro & Iñaki Comas Espadas
    • Program: Doctoral Program in Medicine and Translational Research (University of Barcelona)
    • Date: 26/07/2022
  • Functional and evolutionary genomics of antibiotic resistance in tuberculosis: from biology to global DR-TB control
    • Author: Miguel A. Moreno Molina
    • Supervision: Iñaki Comas Espadas
    • Program: Doctoral Program in Biotechnology (Polytechnic University of Valencia)
    • Date: 03/10/2023