Descripción del proyecto
Glicanos, receptores víricos funcionales y nuevas vacunas antivíricas
Los ensayos actuales no logran determinar la especificidad del receptor y la eficacia de la vacuna del virus de la gripe A, ya que no presentan los receptores del tracto respiratorio superior de los seres humanos. La falta de estos receptores en los hospedadores de laboratorio durante la producción de la vacuna reduce significativamente los rendimientos, lo que da lugar a un desajuste de la vacuna que aumenta la deriva antigénica. El objetivo del proyecto financiado con fondos europeos Sugar-Enable es identificar el receptor funcional de los virus de la gripe A humana. Los investigadores estudiarán cómo cambia la especificidad del glicano debido a la presión inmunitaria, intentando identificar el glicano que utilizan todos los virus de la gripe humana A. Gracias a este conocimiento se pueden desarrollar mejores técnicas de vigilancia, modelos de cultivo e inhibidores basados en la estructura. Finalmente, el proyecto favorecerá nuevas oportunidades para la creación de inhibidores de análogos de glicano y mejores vacunas.
Objetivo
Our current assays to determine the receptor specificity and vaccine efficiency of influenza A virus fail as they do not represent receptors available in the human upper respiratory tract. The lack of these receptors in our laboratory hosts to create vaccines significantly dampen yields, the resulting mismatched vaccines do not afford proper protection and further drive antigenic drift.
The objective of this proposal is to elucidate the functional receptor of human influenza A viruses. By using antigenically drifted viruses, we expect to understand how glycan specificity changes due to immune pressure but it will also lead to the identification of a glycan that is utilized by all human IAV viruses. With this knowledge, better surveillance techniques, culture models and structure-based inhibitors can be developed. Using a novel and sophisticated cell-engineering tool, based on lipidated sugars, we will show functional glycan receptor usage. In addition, I will create cell lines in which human influenza A vaccine viruses grow to high titers without adaptation, thus providing superior protection.
To achieve this goal, I propose to enzymatically synthesize complex glycans (AIM 1), including sialic acid modifications that are found on the respiratory tract epithelial cells of humans and other IAV hosts. Several enzymatic methods and glycan array tools are in place, and thus the chance of success is high. I already set-up preliminary methods for the use of lipidated N-glycan structures and extensive knowledge on SEEL is present in the department (AIM 2). For creating super vaccine producing cell lines I will use genetic approaches that previously have shown to be successful (AIM3).
The systems dealing with sugars enabling function, either for infection or vaccine research, I term sugar-enable, will provide new endeavors to create glycan-analog inhibitors and will bring us steps closer to better vaccines.
Ámbito científico
- natural sciencesbiological sciencesmicrobiologyvirology
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesinfluenza
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesbiological sciencesbiochemistrybiomoleculescarbohydrates
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
3584 CS Utrecht
Países Bajos