Strain-Specific Variability in Viral Kinetics, Cytokine Response, and Cellular Damage in Air-Liquid Cultures of Human Nasal Organoids After Infection with SARS-CoV-2.

Authors

Gina M Aloisio
Trevor J McBride
Letisha Aideyan
Emily M Schultz
Ashley M Murray
Anubama Rajan
Erin G Nicholson
David Henke
Laura Ferlic-Stark
Amal Kambal
Hannah L Johnson
Elina A Mosa
Fabio Stossi
Sarah E Blutt
Pedro A Piedra
Vasanthi Avadhanula

Language

English

Publication Date

10-6-2025

Journal

Viruses

DOI

10.3390/v17101343

PMID

41157615

PMCID

PMC12567804

PubMedCentral® Posted Date

10-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

SARS-CoV-2 variants have demonstrated distinct epidemiological patterns and clinical presentations throughout the COVID-19 pandemic. Understanding variant-specific differences at the respiratory epithelium is crucial for understanding their pathogenesis. Here, we utilized human nasal organoid air-liquid interface (HNO-ALI) cell cultures to compare the viral replication kinetics, innate immune response, and epithelial damage of six different strains of SARS-CoV-2 (B.1.2, WA, Alpha, Beta, Delta, and Omicron). All variants replicated efficiently in HNO-ALIs, but with distinct replication kinetic patterns. The Delta variant exhibited delayed replication kinetics, achieving a steady state at 6 days post-infection compared to 3 days for other variants. Cytokine analysis revealed robust pro-inflammatory and chemoattractant responses (IL-6, IL-8, IP-10, CXCL9, and CXCL11) in WA1, Alpha, Beta, and Omicron infections, while Delta significantly dampened the innate immune response, with no significant induction of IL-6, IP-10, CXCL9, or CXCL11. Immunofluorescence and H&E analysis showed that all variants caused significant ciliary damage, though WA1 and Delta demonstrated less destruction at early time points (3 days post-infection). Together, these data show that, in our HNO-ALI model, the Delta variant employs a distinct "stealth" strategy characterized by delayed replication kinetics and epithelial cell innate immune evasion when compared to other variants of SARS-CoV-2, potentially explaining a mechanism that the Delta variant can use for its enhanced transmissibility and virulence observed clinically. Our findings demonstrate that variant-specific differences at the respiratory epithelium could explain some of the distinct clinical presentations and highlight the utility of the HNO-ALI system for the rapid assessment of emerging variants.

Keywords

Humans, SARS-CoV-2, COVID-19, Virus Replication, Cytokines, Organoids, Immunity, Innate, Nasal Mucosa, Kinetics

Published Open-Access

yes

Recommended Citation

Aloisio, Gina M; McBride, Trevor J; Aideyan, Letisha; et al., "Strain-Specific Variability in Viral Kinetics, Cytokine Response, and Cellular Damage in Air-Liquid Cultures of Human Nasal Organoids After Infection with SARS-CoV-2." (2025). Faculty and Staff Publications. 4822.
https://digitalcommons.library.tmc.edu/baylor_docs/4822