SARS-CoV-2 replication and antiviral responses in bat cells

• Main Author: Aicher, Sophie-Marie
• Other Authors: Signalisation antivirale - Virus sensing and signaling, Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité, Nolwenn Jouvenet
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: HAL CCSD 2022
• Subjects: SARS-CoV-2; Bats; Innate immunity; Reservoir species; Zoonosis; Chauves-souris; Immunité innée; Espèces réservoirs; Zoonoses; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology; Nyctalus noctula
• Online Access: https://theses.hal.science/tel-04405432; https://theses.hal.science/tel-04405432/document; https://theses.hal.science/tel-04405432/file/va_Aicher_Sophie-marie.pdf

Bats are natural reservoirs for numerous emerging zoonotic viruses, including the potential ancestor of SARS-CoV-2. Several immune features found in bats that facilitate antiviral responses and an higher immune tolerance towards viral infections are believed to contribute to their ability to harbor viruses without pathogenesis. Knowledge concerning the molecular interaction of viruses and bat cells is however limited by the lack of bat-specific tools. There is thus a need to develop bat cellular models to understand cell tropism, viral replication and virus-induced cell responses. First, I investigated the ability of primary cells from Rhinolophus and Myotis species, as well as of established and novel cell lines from Myotis myotis, Eptesicus serotinus, Tadarida brasiliensis and Nyctalus noctula, to support SARS-CoV-2 replication. None of these cells were permissive to infection, not even the ones expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), which serves as the viral receptor in many mammalian species including humans. The resistance to infection was overcome by expression of human ACE2 (hACE2) in three cell lines, suggesting that the restriction to viral replication was due to a low expression of bat ACE2 (bACE2) or absence of bACE2 binding in these cells. By contrast, multiple restrictions to viral replication exist in the three N. noctula cell lines since hACE2 expression was not sufficient to permit infection. Infectious virions were produced but not released from hACE2-transduced M. myotis brain cells. E. serotinus brain cells and M. myotis nasal epithelial cells expressing hACE2 efficiently controlled viral replication, which correlated with a potent interferon response. These data highlight the existence of species-specific molecular barriers to SARS-CoV-2 replication in bat cells. Our newly developed chiropteran cellular models are useful tools to investigate the interplay between viruses belonging to the SARS-CoV-2 lineage and their natural reservoir, including the ...