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Viral metagenomics to track, explain and predict the transmission and spatiotemporal spread of Dengue and Chikungunya viruses in Brazil

Grant number: 17/00021-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2017
Effective date (End): August 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Ester Cerdeira Sabino
Grantee:Antonio Charlys da Costa
Home Institution: Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Brazil is hyper-endemic for dengue, with over 10 million cases reported between 2000-2016. The transmission and dissemination of the four serotypes of dengue virus (DENV) is reported in the country through the mosquito vector (Aedes aegypti). Besides DENV, other two virus Chikungunya (CHIKV) and Zika (ZIKV) have already been introduced in Brazil and has caused severe epidemics, but the situation can be complicated even more as these have not yet started the period of rain. This project is a collaboration between researchers from the Institute of Tropical Medicine (IMT/USP), Oxford University (OU) and the Blood Systems Research Institute (BSRI) in an effort to reconstruct in detail the transmission dynamics of circulating viral strains in Brazil, using epidemiological data and the human host to better understand the pathogenesis of these viruses. The infrastructure already established by the Brazilian team has allowed the collection of individual blood samples from different cities in Brazil that will be included in the project and this project will be recruited other cities, which will allow the collection of isolates from current outbreaks of DENV, CHIKV and ZIKV. The aim of this study is to perform the viral metagenomics of samples collected in several Brazilian cities using next-generation sequencing to elucidate and predict the spatial dynamics and transmission of DENV, CHIKV and ZIKV in Brazil. At least 3000 from individuals that total nucleic acids are sequenced, the sequencing order of one or more viruses. The virus that through this approach are not completely sequenced will then be amplified and sequenced the missing parts. The obtained sequences are then subjected to mount "de novo" through a "pipeline" of BSRI for reconstruction of viral genomes, the consensus sequences generated will be submitted to genetic characterization focusing on the identification of transmission networks and viral spread. Then maximum likelihood and Bayesian phylogenetics will be reconstructed to determine the evolutionary relationships of the circulating strains in the national and global contexts. Best fitting nucleotide substitution, molecular clock, and coalescent models will be chosen using harmonic mean estimators, path sampling and stepping stone approaches. Rates of viral lineage movement among populations will be quantified using discrete phylogeographic approaches. Given the latitude and longitude coordinates of each isolate, we will also apply continuous diffusion models and summarize key epidemiological statistics such as dispersal velocity. Coalescent and birth-death skyline models will be used to estimate the rate of epidemic growth through time of different circulating lineages. Rates of synonymous and nonsynonymous changes will be quantified using renaissance counting and more recent algorithms for quantifying molecular adaptation being developed by the Oxford team. Viruses of dengue cases with the worst clinical outcomes will also be sequenced and analysed to see if there is any DENV sequence motif or mutational combination associated with severity. The association between disease severity and mutations will be tested using an association test that takes into account phylogenetic uncertainty. In summary, the study will combine genetic, ecological, clinical, and surveillance data to understand DENV, CHIKV and ZIKV epidemiology. Ultimately, the research proposed here aims to reduce the burden caused by important arbovirus outbreaks in Brazil, with potential benefits for both public health and vaccine development.

Articles published in Agência FAPESP about the scholarship:
Virus that infects pigs in China is found in human patient in Brazil 

Scientific publications (13)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DA COSTA, ANTONIO CHARLYS; LEAL, ELCIO; GILL, DANIELLE; DE PADUA MILAGRES, FLAVIO AUGUSTO; KOMNINAKIS, SHIRLEY VASCONCELOS; BRUSTULIN, RAFAEL; RODRIGUES TELES, MARIA DA APARECIDA; BRITO SAYAO LOBATO, MARCIA CRISTINA ALVES; DAS CHAGAS, ROGERIO TOGISAKI; NEVES DOS SANTOS ABRAO, MARIA DE FATIMA; DE DEUS ALVES SOARES, CASSIA VITORIA; DENG, XUTAO; DELWART, ERIC; SABINO, ESTER CERDEIRA; LUCHS, ADRIANA. Discovery of Cucumis melo endornavirus by deep sequencing of human stool samples in Brazil. VIRUS GENES, v. 55, n. 3, p. 332-338, JUN 2019. Web of Science Citations: 0.
CUNHA, MARIANA SEQUETIN; DA COSTA, ANTONIO CHARLYS; COUTO DE AZEVEDO FERNANDES, NATALIA COELHO; GUERRA, JULIANA MARIOTTI; PEREIRA DOS SANTOS, FABIANA CRISTINA; NOGUEIRA, JULIANA SILVA; D'AGOSTINO, LEANDRO GUARIGLIA; KOMNINAKIS, SHIRLEY VASCONCELOS; WITKIN, STEVEN S.; RESSIO, RODRIGO ALBERGARIA; MAEDA, ADRIANA YURIKA; SILVA VASAMI, FERNANDA GISELE; ABREU KAIGAWA, URSULA MITSUE; DE AZEVEDO, LAIS SAMPAIO; DE SOUZA FACIOLI, PALOMA ALANA; LIMA MACEDO, FERNANDO LUIZ; SABINO, ESTER CERDEIRA; LEAL, ELCIO; DE SOUZA, RENATO PEREIRA. Epizootics due to Yellow Fever Virus in Sao Paulo State, Brazil: viral dissemination to new areas (2016-2017). SCIENTIFIC REPORTS, v. 9, APR 2 2019. Web of Science Citations: 0.
RIBEIRO, GEOVANI DE OLIVEIRA; COSTA MONTEIRO, FRED JULIO; REGO, MARLISSON OCTAVIO DA S.; D'ATHAIDE RIBEIRO, EDCELHA SOARES; DE CASTRO, DANIELA FUNAYAMA; CASEIRO, MARCOS MONTANI; SOUZA MARINHO, ROBSON DOS SANTOS; KOMNINAKIS, SHIRLEY VASCONCELOS; WITKIN, STEVEN S.; DENG, XUTAO; DELWART, ERIC; SABINO, ESTER CERDEIRA; DA COSTA, ANTONIO CHARLYS; LEAL, ELCIO. Detection of RNA-Dependent RNA Polymerase of Hubei Reo-Like Virus 7 by Next-Generation Sequencing in Aedes aegypti and Culex quinquefasciatus Mosquitoes from Brazil. Viruses-Basel, v. 11, n. 2 FEB 2019. Web of Science Citations: 0.
LUCHS, ADRIANA; DA COSTA, ANTONIO CHARLYS; CILLI, AUDREY; VASCONCELOS KOMNINAKIS, SHIRLEY CAVALCANTE; COMPAGNOLI CARMONA, RITA DE CASSIA; BOEN, LAIS; MORILLO, SIMONE GUADAGNUCCI; SABINO, ESTER CERDEIRA; SAMPAIO TAVARES TIMENETSKY, MARIA DO CARMO. Spread of the emerging equine-like G3P[8] DS-1-like genetic backbone rotavirus strain in Brazil and identification of potential genetic variants. JOURNAL OF GENERAL VIROLOGY, v. 100, n. 1, p. 7-25, JAN 2019. Web of Science Citations: 1.
RIBEIRO, GEOVANI DE OLIVEIRA; LUCHS, ADRIANA; DE PADUA MILAGRES, FLAVIO AUGUSTO; KOMNINAKIS, SHIRLEY VASCONCELOS; GILL, DANIELLE ELISE; BRITO SAYAO LOBATO, MARCIA CRISTINA ALVES; BRUSTULIN, RAFAEL; DAS CHAGAS, ROGERIO TOGISAKI; NEVES DOS SANTOS ABRAO, MARIA DE FATIMA; DE DEUS ALVES SOARES, CASSIA VITORIA; WITKIN, STEVEN S.; VILLANOVA, FABIOLA; DENG, XUTAO; SABINO, ESTER CERDEIRA; DELWART, ERIC; DA COSTA, ANTONIO CHARLYS; LEAL, ELCIO. Detection and Characterization of Enterovirus B73 from a Child in Brazil. Viruses-Basel, v. 11, n. 1 JAN 2019. Web of Science Citations: 0.
FERNANDES, LICIA NATAL; COLETTI, THAIS DE MOURA; COSTA MONTEIRO, FRED JULIO; DA SILVA REGO, MARLISSON OCTAVIO; D'ATHAIDE RIBEIRO, EDCELHA SOARES; RIBEIRO, GEOVANI DE OLIVEIRA; SOUZA MARINHO, ROBSON DOS SANTOS; KOMNINAKIS, SHIRLEY VASCONCELOS; WITKIN, STEVEN S.; DENG, XUTAO; DELWART, ERIC; SABINO, ESTER CERDEIRA; LEAL, ELCIO; DA COSTA, ANTONIO CHARLYS. A Novel Highly Divergent Strain of Cell Fusing Agent Virus (CFAV) in Mosquitoes from the Brazilian Amazon Region. Viruses-Basel, v. 10, n. 12 DEC 2018. Web of Science Citations: 0.
DA COSTA, ANTONIO CHARLYS; LUCHS, ADRIANA; DE PADUA MILAGRES, FLAVIO AUGUSTO; KOMNINAKIS, SHIRLEY VASCONCELOS; GILL, DANIELLE ELISE; BRITO SAYAO LOBATO, MARCIA CRISTINA ALVES; BRUSTULIN, RAFAEL; DAS CHAGAS, ROGERIO TOGISAKI; NEVES DOS SANTOS ABRAO, MARIA DE FATIMA; DE DEUS ALVES SOARES, CASSIA VITORIA; DENG, XUTAO; SABINO, ESTER CERDEIRA; DELWART, ERIC; LEAL, ELCIO. Recombination Located over 2A-2B Junction Ribosome Frameshifting Region of Saffold Cardiovirus. Viruses-Basel, v. 10, n. 10 OCT 2018. Web of Science Citations: 0.
CASTRO, TALITA; SABALZA, MAITE; BARBER, CHERYL; ABRAMS, WILLIAM; DA COSTA, ANTONIO CHARLYS; DE PADUA MILAGRES, FLAVIO AUGUSTO; BRAZ-SILVA, PAULO HENRIQUE; MALAMUD, DANIEL; GALLOTTINI, MARINA. Rapid diagnosis of Zika virus through saliva and urine by Loop-mediated isothermal amplification (LAMP). JOURNAL OF ORAL MICROBIOLOGY, v. 10, n. 1 SEP 3 2018. Web of Science Citations: 1.
FARIA, N. R.; KRAEMER, M. U. G.; HILL, S. C.; DE JESUS, J. GOES; AGUIAR, R. S.; IANI, F. C. M.; XAVIER, J.; QUICK, J.; DU PLESSIS, L.; DELLICOUR, S.; THEZE, J.; CARVALHO, R. D. O.; BAELE, G.; WU, C. -H.; SILVEIRA, P. P.; ARRUDA, M. B.; PEREIRA, M. A.; PEREIRA, G. C.; LOURENCO, J.; OBOLSKI, U.; ABADE, L.; VASYLYEVA, T. I.; GIOVANETTI, M.; YI, D.; WEISS, D. J.; WINT, G. R. W.; SHEARER, F. M.; FUNK, S.; NIKOLAY, B.; FONSECA, V.; ADELINO, T. E. R.; OLIVEIRA, M. A. A.; SILVA, M. V. F.; SACCHETTO, L.; FIGUEIREDO, P. O.; REZENDE, I. M.; MELLO, E. M.; SAID, R. F. C.; SANTOS, D. A.; FERRAZ, M. L.; BRITO, M. G.; SANTANA, L. F.; MENEZES, M. T.; BRINDEIRO, R. M.; TANURI, A.; DOS SANTOS, F. C. P.; CUNHA, M. S.; NOGUEIRA, J. S.; ROCCO, I. M.; DA COSTA, A. C.; KOMNINAKIS, S. C. V.; AZEVEDO, V.; CHIEPPE, A. O.; ARAUJO, E. S. M.; MENDONCA, M. C. L.; DOS SANTOS, C. C.; DOS SANTOS, C. D.; MARES-GUIA, A. M.; NOGUEIRA, R. M. R.; SEQUEIRA, P. C.; ABREU, R. G.; GARCIA, M. H. O.; ABREU, A. L.; OKUMOTO, O.; KROON, E. G.; DE ALBUQUERQUE, C. F. C.; LEWANDOWSKI, K.; PULLAN, S. T.; CARROLL, M.; DE OLIVEIRA, T.; SABINO, E. C.; SOUZA, R. P.; SUCHARD, M. A.; LEMEY, P.; TRINDADE, G. S.; DRUMOND, B. P.; FILIPPIS, A. M. B.; LOMAN, N. J.; CAUCHEMEZ, S.; ALCANTARA, L. C. J.; PYBUS, O. G. Genomic and epidemiological monitoring of yellow fever virus transmission potential. Science, v. 361, n. 6405, p. 894+, AUG 31 2018. Web of Science Citations: 16.
DA COSTA, ANTONIO CHARLYS; LUCHS, ADRIANA; DE PADUA MILAGRES, FLAVIO AUGUSTO; KOMNINAKIS, SHIRLEY VASCONCELOS; GILL, DANIELLE ELISE; BRITO SAYAO LOBATO, MARCIA CRISTINA ALVES; BRUSTULIN, RAFAEL; DAS CHAGAS, ROGERIO TOGISAKI; NEVES DOS SANTOS ABRAO, MARIA DE FATIMA; DE DEUS ALVES SOARES, CASSIA VITORIA; DENG, XUTAO; SABINO, ESTER CERDEIRA; DELWART, ERIC; LEAL, ELCIO. Near full length genome of a recombinant (E/D) cosavirus strain from a rural area in the central region of Brazil. SCIENTIFIC REPORTS, v. 8, AUG 17 2018. Web of Science Citations: 0.
LUCHS, ADRIANA; LEAL, ELCIO; KOMNINAKIS, SHIRLEY VASCONCELOS; DE PADUA MILAGRES, FLAVIO AUGUSTO; BRUSTULIN, RAFAEL; RODRIGUES TELES, MARIA DA APARECIDA; GILL, DANIELLE ELISE; DENG, XUTAO; DELWART, ERIC; SABINO, ESTER CERDEIRA; DA COSTA, ANTONIO CHARLYS. Wuhan large pig roundworm virus identified in human feces in Brazil. VIRUS GENES, v. 54, n. 3, p. 470-473, JUN 2018. Web of Science Citations: 1.
ARANHA WATANABE, ARIPUANA SAKURADA; LUCHS, ADRIANA; LEAL, ELCIO; DE PADUA MILAGRES, FLAVIO AUGUSTO; KOMNINAKIS, SHIRLEY VASCONCELOS; GILL, DANIELLE ELISE; BRITO SAYAO LOBATO, MARCIA CRISTINA ALVES; BRUSTULIN, RAFAEL; DAS CHAGAS, ROGERIO TOGISAKI; NEVES DOS SANTOS ABRAO, MARIA DE FATIMA; DE DEUS ALVES SOARES, CASSIA VITORIA; DENG, XUTAO; SABINO, ESTER CERDEIRA; DELWART, ERIC; DA COSTA, ANTONIO CHARLYS. Complete Genome Sequences of Six Human Bocavirus Strains from Patients with Acute Gastroenteritis in the North Region of Brazil. MICROBIOLOGY RESOURCE ANNOUNCEMENTS, v. 6, n. 17 APR 2018. Web of Science Citations: 0.
FARIA, NUNO R.; DA COSTA, ANTONIO CHARLYS; LOURENCO, JOSE; LOUREIRO, PAULA; LOPES, MARIA ESTHER; RIBEIRO, ROBERTO; ALENCAR, CECILIA SALETE; KRAEMER, MORITZ U. G.; VILLABONA-ARENAS, CHRISTIAN J.; WU, CHIEH-HSI; THEZE, JULIEN; KHAN, KAMRAN; BRENT, SHANNON E.; ROMANO, CAMILA; DELWART, ERIC; CUSTER, BRIAN; BUSCH, MICHAEL P.; PYBUS, OLIVER G.; SABINO, ESTER C.; EPIDEMIOLOGY, NHLBI RECIPIENT; STUDY, DONOR EVALUATION. Genomic and epidemiological characterisation of a dengue virus outbreak among blood donors in Brazil. SCIENTIFIC REPORTS, v. 7, NOV 9 2017. Web of Science Citations: 7.

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