Human airway and nasal organoids reveal escalating replicative fitness of SARS-CoV-2 emerging variants

TY - JOUR

T1 - Human airway and nasal organoids reveal escalating replicative fitness of SARS-CoV-2 emerging variants

AU - Li, Cun

AU - Huang, Jingjing

AU - Yu, Yifei

AU - Wan, Zhixin

AU - Chiu, Man Chun

AU - Liu, Xiaojuan

AU - Zhang, Shuxin

AU - Cai, Jian-Piao

AU - Chu, Hin

AU - Li, Gang

AU - Chan, Jasper Fuk-Woo

AU - To, Kelvin Kai-Wang

AU - Yang, Zifeng

AU - Jiang, Shibo

AU - Yuen, Kwok-Yung

AU - Clevers, Hans

AU - Zhou, Jie

PY - 2023/4/25

Y1 - 2023/4/25

N2 - The high transmissibility of SARS-CoV-2 Omicron subvariants was generally ascribed to immune escape. It remained unclear whether the emerging variants have gradually acquired replicative fitness in human respiratory epithelial cells. We sought to evaluate the replicative fitness of BA.5 and earlier variants in physiologically active respiratory organoids. BA.5 exhibited a dramatically increased replicative capacity and infectivity than B.1.1.529 and an ancestral strain wildtype (WT) in human nasal and airway organoids. BA.5 spike pseudovirus showed a significantly higher entry efficiency than that carrying WT or B.1.1.529 spike. Notably, we observed prominent syncytium formation in BA.5-infected nasal and airway organoids, albeit elusive in WT- and B.1.1.529-infected organoids. BA.5 spike-triggered syncytium formation was verified by lentiviral overexpression of spike in nasal organoids. Moreover, BA.5 replicated modestly in alveolar organoids, with a significantly lower titer than B.1.1.529 and WT. Collectively, the higher entry efficiency and fusogenic activity of BA.5 spike potentiated viral spread through syncytium formation in the human airway epithelium, leading to enhanced replicative fitness and immune evasion, whereas the attenuated replicative capacity of BA.5 in the alveolar organoids may account for its benign clinical manifestation.

AB - The high transmissibility of SARS-CoV-2 Omicron subvariants was generally ascribed to immune escape. It remained unclear whether the emerging variants have gradually acquired replicative fitness in human respiratory epithelial cells. We sought to evaluate the replicative fitness of BA.5 and earlier variants in physiologically active respiratory organoids. BA.5 exhibited a dramatically increased replicative capacity and infectivity than B.1.1.529 and an ancestral strain wildtype (WT) in human nasal and airway organoids. BA.5 spike pseudovirus showed a significantly higher entry efficiency than that carrying WT or B.1.1.529 spike. Notably, we observed prominent syncytium formation in BA.5-infected nasal and airway organoids, albeit elusive in WT- and B.1.1.529-infected organoids. BA.5 spike-triggered syncytium formation was verified by lentiviral overexpression of spike in nasal organoids. Moreover, BA.5 replicated modestly in alveolar organoids, with a significantly lower titer than B.1.1.529 and WT. Collectively, the higher entry efficiency and fusogenic activity of BA.5 spike potentiated viral spread through syncytium formation in the human airway epithelium, leading to enhanced replicative fitness and immune evasion, whereas the attenuated replicative capacity of BA.5 in the alveolar organoids may account for its benign clinical manifestation.

KW - Humans

KW - SARS-CoV-2/genetics

KW - COVID-19/genetics

KW - Nose

KW - Organoids

KW - Spike Glycoprotein, Coronavirus/genetics

KW - Antibodies, Neutralizing

KW - Antibodies, Viral

U2 - 10.1073/pnas.2300376120

DO - 10.1073/pnas.2300376120

M3 - Article

C2 - 37068258

SN - 0027-8424

VL - 120

SP - e2300376120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 17

ER -