SARS-CoV-2 Omicron Induces Enhanced Mucosal Interferon Response Compared to other Variants of Concern, Associated with Restricted Replication in Human Lung Tissues
Or Alfi,
Marah Hamdan,
Ori Wald,
Arkadi Yakirevitch,
Ori Wandel,
Esther Oiknine-Djian,
Ben Gvili,
Hadas Knoller,
Noa Rozendorn,
Hadar Golan Berman,
Sheera Adar,
Olesya Vorontsov,
Michal Mandelboim,
Zichria Zakay-Rones,
Menachem Oberbaum,
Amos Panet,
Dana G. Wolf
Affiliations
Or Alfi
Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
Marah Hamdan
Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
Ori Wald
Department of Cardiothoracic Surgery, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
Arkadi Yakirevitch
Department of Otorhinolaryngology, Sheba Medical Center, Ramat Gan 52621, Israel
Ori Wandel
Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
Esther Oiknine-Djian
Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
Ben Gvili
Department of Otorhinolaryngology, Sheba Medical Center, Ramat Gan 52621, Israel
Hadas Knoller
Department of Otorhinolaryngology, Sheba Medical Center, Ramat Gan 52621, Israel
Noa Rozendorn
Department of Otorhinolaryngology, Sheba Medical Center, Ramat Gan 52621, Israel
Hadar Golan Berman
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel
Sheera Adar
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel
Olesya Vorontsov
Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
Michal Mandelboim
Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan 52621, Israel
Zichria Zakay-Rones
Department of Biochemistry, Institute for Medical Research Israel Canada, Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel
Menachem Oberbaum
The Center for Integrative Complementary Medicine, Shaare Zedek Medical Center, Jerusalem 9103102, Israel
Amos Panet
Department of Biochemistry, Institute for Medical Research Israel Canada, Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel
Dana G. Wolf
Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
SARS-CoV-2 Omicron variant has been characterized by decreased clinical severity, raising the question of whether early variant-specific interactions within the mucosal surfaces of the respiratory tract could mediate its attenuated pathogenicity. Here, we employed ex vivo infection of native human nasal and lung tissues to investigate the local-mucosal susceptibility and innate immune response to Omicron compared to Delta and earlier SARS-CoV-2 variants of concern (VOC). We show that the replication of Omicron in lung tissues is highly restricted compared to other VOC, whereas it remains relatively unchanged in nasal tissues. Mechanistically, Omicron induced a much stronger antiviral interferon response in infected tissues compared to Delta and earlier VOC-a difference, which was most striking in the lung tissues, where the innate immune response to all other SARS-CoV-2 VOC was blunted. Notably, blocking the innate immune signaling restored Omicron replication in the lung tissues. Our data provide new insights to the reduced lung involvement and clinical severity of Omicron.
