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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

Aloisio et al., Viruses, doi:10.3390/v17101343, Oct 2025
https://c19early.org/aloisio.html
Ex vivo study comparing the viral kinetics, immune response, and cellular damage of six different SARS-CoV-2 strains (B.1.2, WA1, Alpha, Beta, Delta, and Omicron) in human nasal organoid air-liquid interface (HNO-ALI) cultures. Authors found that the Delta variant employs a unique "stealth" strategy, showing delayed replication kinetics and a dampened innate immune response compared to the other variants. While most variants reached peak viral load by 3 days post-infection, Delta took 6 days to reach a similar level. The WA1, Alpha, Beta, and Omicron variants induced robust pro-inflammatory and chemoattractant cytokine responses, but the Delta variant did not significantly induce key cytokines such as IL-6, IP-10, CXCL9, or CXCL11. All variants caused significant damage to ciliated cells, though the Delta and WA1 strains appeared less destructive at early time points.
Aloisio et al., 6 Oct 2025, peer-reviewed, 16 authors. Contact: ppiedra@bcm.edu (corresponding author), gina.aloisio@bcm.edu, avadhanu@bcm.edu.
Ex vivo studies are an important part of preclinical research, however results may be very different in vivo.
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
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
Viruses, doi:10.3390/v17101343
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.
Supplementary Materials: The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/v17101343/s1 . File S1: Supplementary Figures; File S2: Supplementary Data. Author Contributions: G.M.A. designed the project, performed experiments, analyzed data, and wrote the manuscript draft. T.J.M., L.A., E.M.S., A.M.M. and A.R. performed infections, viral kinetics and cytokine measurements, and imaging, and edited the manuscript. E.G.N. consented subjects, obtained nasal washes from subjects, and edited the manuscript. D.H. and L.F.-S. performed the statistical analysis and edited the manuscript. A.K. provided organoid cultures and edited the manuscript. H.L.J., E.A.M. and F.S. performed microscopy and edited the manuscript. S.E.B. supervised established organoid cultures and edited the manuscript. P.A.P. and V.A. designed the project, analyzed data, obtained funding, and wrote and edited the manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors declare no conflicts of interest.
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DOI record: { "DOI": "10.3390/v17101343", "ISSN": [ "1999-4915" ], "URL": "http://dx.doi.org/10.3390/v17101343", "abstract": "<jats:p>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&amp;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.</jats:p>", "alternative-id": [ "v17101343" ], "author": [ { "ORCID": "https://orcid.org/0000-0003-0710-5094", "affiliation": [ { "name": "Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA" }, { "name": "Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA" } ], "authenticated-orcid": false, "family": "Aloisio", "given": "Gina M.", "sequence": "first" }, { "affiliation": [ { "name": "Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA" } ], "family": "McBride", "given": "Trevor J.", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, 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