Glycosphingolipids are essential entry factors for non-influenza orthomyxoviruses

Abstract

Thogotoviruses and quaranjaviruses are arthropod-borne orthomyxoviruses that circulate widely in wildlife and domestic animals and include several zoonotic members. Despite their close phylogenetic relationship to influenza viruses, the mechanisms underlying their replication remain poorly understood, and the host factors mediating viral entry are unknown. Here, we performed genome-wide loss-of-function CRISPR-Cas9 screens using replication-competent recombinant vesicular stomatitis viruses expressing thogoto-and quaranjavirus glycoproteins to identify cellular determinants of viral entry. These screens identified the glycosphingolipid (GSL) biosynthesis pathway as a key regulator of viral entry, with the upstream enzyme uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) emerging as a central host entry factor. Pharmacological inhibition of UGCG impaired thogoto-and quaranjavirus entry. The importance of GSL biosynthesis for thogotovirus replication was further validated using multiple thogotovirus isolates. Together, our findings establish GSLs as critical host entry factors for non-influenza orthomyxoviruses and identify UGCG as a potential target for antiviral intervention.

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BibTeX RIS

BibTeX

@article{lozanomontalba2026glycosphingolipids,
  title = {{Glycosphingolipids are essential entry factors for non-influenza orthomyxoviruses}},
  author = {Lorena Lozano-Montalbá and Zoé Denis and Valérie Courgnaud and Jorge Moreno-García and Karim Majzoub and Rafael Sanjuán and Jérémy Dufloo},
  journal = {Journal of General Virology},
  year = {2026},
  month = aug,
  doi = {10.1099/jgv.0.002315},
  url = {https://hal.science/hal-05753424v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Glycosphingolipids are essential entry factors for non-influenza orthomyxoviruses
AU  - Lorena Lozano-Montalbá
AU  - Zoé Denis
AU  - Valérie Courgnaud
AU  - Jorge Moreno-García
AU  - Karim Majzoub
AU  - Rafael Sanjuán
AU  - Jérémy Dufloo
PY  - 2026
DA  - 2026/08/13
JO  - Journal of General Virology
DO  - 10.1099/jgv.0.002315
UR  - https://hal.science/hal-05753424v1
AB  - Thogotoviruses and quaranjaviruses are arthropod-borne orthomyxoviruses that circulate widely in wildlife and domestic animals and include several zoonotic members. Despite their close phylogenetic relationship to influenza viruses, the mechanisms underlying their replication remain poorly understood, and the host factors mediating viral entry are unknown. Here, we performed genome-wide loss-of-function CRISPR-Cas9 screens using replication-competent recombinant vesicular stomatitis viruses expressing thogoto-and quaranjavirus glycoproteins to identify cellular determinants of viral entry. These screens identified the glycosphingolipid (GSL) biosynthesis pathway as a key regulator of viral entry, with the upstream enzyme uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) emerging as a central host entry factor. Pharmacological inhibition of UGCG impaired thogoto-and quaranjavirus entry. The importance of GSL biosynthesis for thogotovirus replication was further validated using multiple thogotovirus isolates. Together, our findings establish GSLs as critical host entry factors for non-influenza orthomyxoviruses and identify UGCG as a potential target for antiviral intervention.
SN  - 0022-1317
SN  - 1465-2099
ER  -

Abstract

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