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The use of antibodies that neutralize infection at a post-attachment step for the development of innovative immunotherapeutic strategies exemplified for selective destruction of Zika-infected human cells.

Abstract

Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. It is transmitted to humans by the principle mosquito species Aedes aegypti, characterized by its remarkable ability to rapidly adapt to changing environments allowing them to bred in urban areas, flourishing in impoverished and crowded areas with no piped water and poorly collected garbage. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. Effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. The ZIKV genome consists of a single-stranded positive sense RNA molecule with 10794 kb of length with 2 flanking non-coding regions (52 and 32 NCR) and a single long open reading frame encoding a polyprotein: 52-C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-32 that is cleaved into capsid (C), precursor of membrane (prM), envelope (E) and seven non-structural proteins (NS) (Figure 1).The E protein (H53 kDa) is the major virion surface protein being involved in various aspects of the viral cycle, mediating binding and membrane fusion. We intend to identify antibodies able to neutralize infectivity at a post-attachment step. The antibody-secreting cells corresponding to the antibodies of interest will have their variable genes sequenced. Recombinant antibody technologies would be used in collaboration with the group of Prof. Barth (UCT, South Africa) to select and engineer antibody fragments specific to the relevant epitopes. Prof. Barth has a track record on the generation of knowledge based recombinant immunodiagnostics and immunotherapeutics especially for proliferative diseases. This collaboration project would allow to rely on this expertise and to translate it to specific detection and elimination of infected cells. The most promising recombinant antibodies identified would be further modified by protein engineering to provide ZIKV specific next generation immunodiagnostics and therapeutics. General applicability of the recombinant antibody technologies as well as cross-reactivity, and mechanistic similarities of epitopes would in the future allow to extend the methodology to other flaviruses in particular (e.g. SLEV, WNV, EOCV, etc.) and arboviruses (e.g. alphaviruses and bunyaviruses) in general. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:

Scientific publications (5)
(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)
CUNHA, MARIELTON DOS PASSOS; DUARTE-NETO, AMARO NUNES; POUR, SHAHAB ZAKI; HAJJAR, LUDHMILA ABRAHAO; FRASSETTO, FERNANDO PEREIRA; DOLHNIKOFF, MARISA; DO NASCIMENTO SALDIVA, PAULO HILARIO; DE ANDRADE ZANOTTO, PAOLO MARINHO. Systemic dengue infection associated with a new dengue virus type 2 introduction in Brazil - a case report. BMC INFECTIOUS DISEASES, v. 21, n. 1 APR 1 2021. Web of Science Citations: 0.
DIENG, IDRISSA; DIARRA, MARYAM; DIAGNE, MOUSSA MOISE; FAYE, MARTIN; DIOR NDIONE, MARIE HENRIETTE; BA, YAMAR; DIOP, MAMADOU; NDIAYE, EL HADJI; MARINHO DE ANDRADE ZANOTTO, PAOLO; DIOP, BOLY; NDIAYE, MAMADOU; BOUSSO, ABDOULAYE; DIA, NDONGO; DIALLO, MAWLOUTH; BARRY, ALIOU; FALL, GAMOU; LOUCOUBAR, CHEIKH; SALL, AMADOU ALPHA; FAYE, OUSMANE; FAYE, OUMAR. Field Deployment of a Mobile Biosafety Laboratory Reveals the Co-Circulation of Dengue Viruses Serotype 1 and Serotype 2 in Louga City, Senegal, 2017. JOURNAL OF TROPICAL MEDICINE, v. 2021, APR 1 2021. Web of Science Citations: 0.
DIENG, IDRISSA; DOS PASSOS CUNHA, MARIELTON; DIAGNE, MOUSSA MOISE; SEMBENE, PAPE MBACKE; DE ANDRADE ZANOTTO, PAOLO MARINHO; FAYE, OUSMANE; FAYE, OUMAR; SALL, AMADOU ALPHA. Origin and Spread of the Dengue Virus Type 1, Genotype V in Senegal, 2015-2019. Viruses-Basel, v. 13, n. 1 JAN 2021. Web of Science Citations: 0.
CUNHA, MARIELTON DOS PASSOS; IOSHINO, RAFAELLA SAYURI; COSTA-DA-SILVA, ANDRE LUIS; PETERSEN, VIVIAN; CAPURRO, MARGARETH LARA; ZANOTTO, PAOLO MARINHO DE ANDRADE. A Metagenomic Approach Identified a Novel Phasi Charoen- Like Virus Coinfecting a Chikungunya Virus-Infected Aedes aegypti Mosquito in Brazil. MICROBIOLOGY RESOURCE ANNOUNCEMENTS, v. 9, n. 31 JUL 2020. Web of Science Citations: 1.
CUNHA, MARIELTON DOS PASSOS; DUARTE-NETO, AMARO NUNES; POUR, SHAHAB ZAKI; ORTIZ-BAEZ, AYDA SUSANA; CERNY, JIRI; DE SOUZA PEREIRA, BARBARA BRITO; BRACONI, CARLA TORRES; HO, YEH-LI; PERONDI, BEATRIZ; SZTAJNBOK, JAQUES; FERREIRA ALVES, VENANCIO AVANCINI; DOLHNIKOFF, MARISA; HOLMES, EDWARD C.; NASCIMENTO SALDIVA, PAULO HILARIO; DE ANDRADE ZANOTTO, PAOLO MARINHO. Origin of the Sao Paulo Yellow Fever epidemic of 2017-2018 revealed through molecular epidemiological analysis of fatal cases. SCIENTIFIC REPORTS, v. 9, DEC 31 2019. Web of Science Citations: 0.

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