SARS-CoV-2 Omicron Envelope T9I adaptation confers resistance to autophagy

Susanne Klute; Rayhane Nchioua; Arne Cordsmeier; Jyoti Vishwakarma; Lennart Koepke; Hala Alshammary; Christoph Jung; Maximilian Hirschenberger; Helene Hoenigsperger; Jana-Romana Fischer; Rinu Sivarajan; Fabian Zech; Steffen Stenger; Ruth Serra-Moreno; Ana Silvia Gonzalez-Reiche; Emilia Mia Sordillo; Harm van Bakel; Viviana R. Simon; Frank Kirchhoff; Timo Jacob; Dorota Kmieć; Andreas Pichlmair; Armin Ensser; Konstantin M. J. Sparrer

doi:10.1016/j.isci.2025.112974

MicrobiologyiScienceJun 20, 2025

Peer-reviewed journal article

SARS-CoV-2 Omicron Envelope T9I adaptation confers resistance to autophagy

Susanne Klute iD, Rayhane Nchioua iD, Arne Cordsmeier iD, Jyoti Vishwakarma iD, Lennart Koepke iD, Hala Alshammary iD, Christoph Jung iD, Maximilian Hirschenberger iD, Helene Hoenigsperger iD, Jana-Romana Fischer, Rinu Sivarajan iD, Fabian Zech iD, Steffen Stenger iD, Ruth Serra-Moreno iD, Ana Silvia Gonzalez-Reiche iD, Emilia Mia Sordillo iD, Harm van Bakel iD, Viviana R. Simon iD, Frank Kirchhoff iD, Timo Jacob iD, Dorota Kmieć iD, Andreas Pichlmair iD, Armin Ensser iD, Konstantin M. J. Sparrer iD

Abstract

To date, five variants of concern (VOCs) of SARS-CoV-2 have emerged that show increased fitness and/or immune evasion. While the continuously evolving escape from humoral immune responses has been analyzed in detail, adaptation of SARS-CoV-2 to human innate immune defenses such as autophagy is less understood. Here, we demonstrate that mutation T9I in the structural envelope (E) protein confers autophagy resistance of Omicron VOCs (BA.1, BA.5 and XBB.1.5) compared to 2020 SARS-CoV-2 or the Delta VOC. Mechanistic analyses revealed that Omicron-associated E T9I shows increased inhibition of autophagic flux and colocalization/interaction with autophagosomes, thus shielding incoming SARS-CoV-2 S pseudotyped virions from autophagy. Rare Omicron isolates carrying ancestral E T9 remain sensitive towards autophagy whereas recombinant early 2020 SARS-CoV-2 expressing E T9I shows increases resistance against autophagy. Our data indicate that the E T9I mutation drives autophagy resistance of the Omicron variants and thus may have contributed to their effective spread.

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