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Initiale Schritte der Phlebovirus-Infektion

Fachliche Zuordnung Virologie
Förderung Förderung von 2018 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 407056042
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

The Phlebovirus genus (Bunyavirales order) constitutes a group of viruses mainly transmitted by ticks and phlebotomine sandflies. Many phleboviruses cause severe diseases – often fatal – and have been reported on different continents, including Western Europe. The increasing number of outbreaks and the apparent wide distribution of reservoirs of sandflies and ticks demonstrate that these viruses must be taken seriously as emerging disease agents. In this context, there is interest in using the prototype phleboviruses Toscana (TOSV) and Uukuniemi (UUKV), respectively transmitted by sandflies and ticks, to understand the biology of these emerging pathogens. Here, the Lozach lab (Heidelberg, DFG) and the Rey lab (Pasteur, ANR) synergized their efforts to investigate the infectious entry process of phleboviruses. The preliminary data of the Lozach lab suggest that UUKV is not inactivated following exposure to low pH, and the Rey lab has identified a not-yet-published intermediate structure of the UUKV envelope fusion glycoprotein. Together, these observations suggest that the priming process for phlebovirus-induced membrane fusion may be fundamentally distinct from that of well-studied class II viruses such as flaviviruses and alphaviruses. Within Aim 1 of this project, we performed a lipidomics analysis with mass spectrometry and found that glucosylceramide (GlcCer) is a major structural determinant of UUKV virions necessary for binding to various cell types. It appeared that UUKV infection results in the overexpression of glucosylceramide synthase and the specific accumulation of GlcCer and its subsequent incorporation into viral progeny. Our results pinpoint a novel type of virus-receptor interaction, involving the recognition of glycolipids in the virion envelope by host cell receptors. Using a combination of X-ray and AlphaFold2 analysis of the viral Gn/Gc glycoprotein ectodomain, we found that TOSV and UUKV belong to the group of viruses with a class II fusion protein. These results are in line with other known structures for other phleboviruses. As part of Aim 3, we provided a comprehensive view of the infectious entry program of TOSV. Our data indicated that TOSV is a late-penetrating virus, a group of viruses that relies on late endosomal maturation for infection. Strikingly, the particles remained infectious after entering late endosomes with a pH below the fusion threshold for long periods. Our study also confirmed that the atypical use of vacuolar acidity by UUKV to enter host cells is shared with other phleboviruses and bunyaviruses, including TOSV, Rift Valley fever virus, and Germiston virus. Overall, the results gained here point towards the remarkable adaptability of phleboviruses and other bunyaviruses to endosomal acidity that certainly confers to these viruses the advantage of trial and error in endocytosis pathways until they reach endosomes suitable for viral fusion. As such, bunyaviruses have likely found a way to expand their possibilities of entering and infecting host cells, and in turn, facilitating their propagation.

Projektbezogene Publikationen (Auswahl)

 
 

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