{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:05:34Z","timestamp":1790316334709,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T00:00:00Z","timestamp":1743292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of California Davis Schools of Veterinary Medicine and Medicine","award":["U42OD012210"],"award-info":[{"award-number":["U42OD012210"]}]},{"name":"University of California Davis Schools of Veterinary Medicine and Medicine","award":["NIH R01DC019769"],"award-info":[{"award-number":["NIH R01DC019769"]}]},{"name":"US National Institute of Health (NIH) Office of the Director DCM\/ORIP\/Division of Program Coordination, Planning, and Strategic Initiatives","award":["U42OD012210"],"award-info":[{"award-number":["U42OD012210"]}]},{"name":"US National Institute of Health (NIH) Office of the Director DCM\/ORIP\/Division of Program Coordination, Planning, and Strategic Initiatives","award":["NIH R01DC019769"],"award-info":[{"award-number":["NIH R01DC019769"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The global impact of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), persists in part due to the emergence of new variants. Understanding variant-specific infection dynamics and pathogenesis in murine models is crucial for identifying phenotypic changes and guiding the development of countermeasures. To address the limitations of earlier studies that investigated only a few variants or used small sample sizes, we evaluated clinical disease, infection kinetics, viral titers, cellular localization, and histopathologic changes in the lungs and brains of transgenic B6.Cg-Tg(K18-ACE2)2Prlmn\/J (\u201cK18\u201d) and corresponding genetic control (C57BL\/6J) mice expressing human angiotensin-converting enzyme 2 (hACE2). Six SARS-CoV-2 variants were assessed: B.1 (WA1-like), alpha, beta, delta, omicron, and omicron XBB.1.5, using cohorts of \u226518 mice. Following intranasal inoculation with B.1, alpha, beta, or delta variants, K18 mice experienced rapid weight loss and reached euthanasia criteria by 5\u20136 days post-inoculation (dpi). In contrast, K18 mice inoculated with both omicron variants recovered to their starting weight within 4\u20136 dpi. Infectious SARS-CoV-2 was detected in the oropharynx at 1 and2 dpi, in the lungs at 2, 4, and 6 dpi, and in the brain at 4 and 6 dpi for all variants except omicron. SARS-CoV-2 nucleoprotein was detected, and interstitial pneumonia of varying severity was observed in K18 mice infected with all variants. Brain lesions were identified in mice infected with the B.1, beta, and delta variants 6 dpi. As K18 mice express hACE2 in the brain\u2014a feature not present in humans\u2014we also compared infection dynamics of three variants to those of a mouse-adapted WA1 strain in C57BL\/6J mice lacking the human ACE2 gene. C57BL\/6J mice did not experience lethal disease, exhibited milder pneumonia, and had no evidence of neuroinvasion despite similar infection kinetics to K18 mice. These findings demonstrate contrasting phenotypes across the two models and reduced tropism and pathology of omicron compared to earlier variants in both models. This comprehensive analysis of SARS-CoV-2 variants in two mouse models provides valuable insights for model and variant selection for future studies.<\/jats:p>","DOI":"10.3390\/v17040500","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:21:04Z","timestamp":1743398464000},"page":"500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Severe Acute Respiratory Syndrome Coronavirus 2 Variant Infection Dynamics and Pathogenesis in Transgenic K18-hACE2 and Inbred Immunocompetent C57BL\/6J Mice"],"prefix":"10.3390","volume":"17","author":[{"given":"Hongwei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4313-9489","authenticated-orcid":false,"given":"Brianna M.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1986-6109","authenticated-orcid":false,"given":"Talia S.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4704-9533","authenticated-orcid":false,"given":"Christopher M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin C. K.","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Mouse Biology Program, University of California, Davis, CA 95616, USA"},{"name":"Department of Surgery, School of Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7453-6508","authenticated-orcid":false,"given":"Qizhi","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0718-5146","authenticated-orcid":false,"given":"Lark L.","family":"Coffey","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,30]]},"reference":[{"key":"ref_1","unstructured":"(2024, October 22). COVID-19 Cases|WHO COVID-19 Dashboard. Available online: https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1001\/jama.2021.2294","article-title":"SARS-CoV-2 Variants of Concern in the United States-Challenges and Opportunities","volume":"325","author":"Walensky","year":"2021","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41579-022-00713-0","article-title":"SARS-CoV-2 Pathogenesis","volume":"20","author":"Lamers","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","unstructured":"World Health Organization (2025). Post COVID-19 Condition (Long COVID), World Health Organization."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tarr\u00e9s-Freixas, F., Trinit\u00e9, B., Pons-Gr\u00edfols, A., Romero-Durana, M., Riveira-Mu\u00f1oz, E., \u00c1vila-Nieto, C., P\u00e9rez, M., Garcia-Vidal, E., Perez-Zsolt, D., and Mu\u00f1oz-Basagoiti, J. (2022). Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.840757"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12982-024-00140-x","article-title":"Evolution and Implications of SARS-CoV-2 Variants in the Post-Pandemic Era","volume":"21","author":"Manirambona","year":"2024","journal-title":"Discov. Public Health"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mendiola-Pastrana, I.R., L\u00f3pez-Ortiz, E., R\u00edo de la Loza-Zamora, J.G., Gonz\u00e1lez, J., G\u00f3mez-Garc\u00eda, A., and L\u00f3pez-Ortiz, G. (2022). SARS-CoV-2 Variants and Clinical Outcomes: A Systematic Review. Life, 12.","DOI":"10.3390\/life12020170"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hirabara, S.M., Serdan, T.D.A., Gorjao, R., Masi, L.N., Pithon-Curi, T.C., Covas, D.T., Curi, R., and Durigon, E.L. (2022). SARS-CoV-2 Variants: Differences and Potential of Immune Evasion. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.781429"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Singh, H., Dahiya, N., Yadav, M., and Sehrawat, N. (2022). Emergence of SARS-CoV-2 New Variants and Their Clinical Significance. Can. J. Infect. Dis. Med. Microbiol., 2022.","DOI":"10.1155\/2022\/7336309"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"383","DOI":"10.30802\/AALAS-CM-21-000031","article-title":"Mouse Models for the Study of SARS-CoV-2 Infection","volume":"71","author":"Knight","year":"2021","journal-title":"Comp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Park, J.-G., Pino, P.A., Akhter, A., Alvarez, X., Torrelles, J.B., and Martinez-Sobrido, L. (2022). Animal Models of COVID-19: Transgenic Mouse Model. Methods Mol. Biol., 2452.","DOI":"10.1007\/978-1-0716-2111-0_16"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kim, S.-H., Kim, J., Jang, J.Y., Noh, H., Park, J., Jeong, H., Jeon, D., Uhm, C., Oh, H., and Cho, K. (2022). Mouse Models of Lung-Specific SARS-CoV-2 Infection with Moderate Pathological Traits. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1105713"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Dedoni, S., Avdoshina, V., Camoglio, C., Siddi, C., Fratta, W., Scherma, M., and Fadda, P. (2022). K18- and CAG-hACE2 Transgenic Mouse Models and SARS-CoV-2: Implications for Neurodegeneration Research. Molecules, 27.","DOI":"10.3390\/molecules27134142"},{"key":"ref_14","unstructured":"(2024, July 20). SARS-CoV-2 Immunity in Animal Models | Cellular & Molecular Immunology. Available online: https:\/\/www.nature.com\/articles\/s41423-023-01122-w."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1128\/JVI.02012-06","article-title":"Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus","volume":"81","author":"McCray","year":"2007","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yinda, C.K., Port, J.R., Bushmaker, T., Owusu, I.O., Purushotham, J.N., Avanzato, V.A., Fischer, R.J., Schulz, J.E., Holbrook, M.G., and Hebner, M.J. (2021). K18-hACE2 Mice Develop Respiratory Disease Resembling Severe COVID-19. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009195"},{"key":"ref_17","unstructured":"(2024, October 25). A Longitudinal Molecular and Cellular Lung Atlas of Lethal SARS-CoV-2 Infection in K18-hACE2 Transgenic Mice\u2014PubMed, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/38118400\/."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Aw, Z.Q., Mok, C.K., Wong, Y.H., Chen, H., Mak, T.M., Lin, R.T.P., Lye, D.C., Tan, K.S., and Chu, J.J.H. (2022). Early Pathogenesis Profiles across SARS-CoV-2 Variants in K18-hACE2 Mice Revealed Differential Triggers of Lung Damages. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.950666"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6559","DOI":"10.1038\/s41467-021-26803-w","article-title":"SARS-CoV-2 B.1.1.7 (Alpha) and B.1.351 (Beta) Variants Induce Pathogenic Patterns in K18-hACE2 Transgenic Mice Distinct from Early Strains","volume":"12","author":"Radvak","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"He, Y., Henley, J., Sell, P., and Comai, L. (2023). Differential Outcomes of Infection by Wild-Type SARS-CoV-2 and the B.1.617.2 and B.1.1.529 Variants of Concern in K18-hACE2 Transgenic Mice. Viruses, 16.","DOI":"10.1101\/2023.09.08.556906"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kuruppuarachchi, K.A.P.P., Jang, Y., and Seo, S.H. (2022). Comparison of the Pathogenicity of SARS-CoV-2 Delta and Omicron Variants by Analyzing the Expression Patterns of Immune Response Genes in K18-hACE2 Transgenic Mice. Front. Biosci. (Landmark Ed.), 27.","DOI":"10.31083\/j.fbl2711316"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Weiss, C.M., Liu, H., Ball, E.E., Hoover, A.R., Wong, T.S., Wong, C.F., Lam, S., Hode, T., Keel, M.K., and Levenson, R.M. (2023). N-Dihydrogalactochitosan Reduces Mortality in a Lethal Mouse Model of SARS-CoV-2. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0289139"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Liu, G., Zhang, M., Wu, B., Zhang, C., Wang, Y., Han, X., Wang, R., Li, L., Wei, Y., and Sun, Y. (2024). A Highly Susceptible hACE2-Transgenic Mouse Model for SARS-CoV-2 Research. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1348405"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"40","DOI":"10.5501\/wjv.v11.i1.40","article-title":"Animal Models for SARS-CoV-2 and SARS-CoV-1 Pathogenesis, Transmission and Therapeutic Evaluation","volume":"11","author":"Saravanan","year":"2022","journal-title":"World J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/s41590-020-0778-2","article-title":"SARS-CoV-2 Infection of hACE2 Transgenic Mice Causes Severe Lung Inflammation and Impaired Function","volume":"21","author":"Winkler","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.tcm.2022.04.004","article-title":"COVID-19 and the Brain","volume":"32","author":"Hingorani","year":"2022","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Davis, M., Voss, K., Turnbull, J.B., Gustin, A.T., Knoll, M., Muruato, A., Hsiang, T.-Y., Dinnon, K.H., Leist, S.R., and Nickel, K. (2022). A C57BL\/6 Mouse Model of SARS-CoV-2 Infection Recapitulates Age- and Sex-Based Differences in Human COVID-19 Disease and Recovery. Res. Sq., 11.","DOI":"10.21203\/rs.3.rs-2194450\/v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.cell.2020.09.050","article-title":"A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice","volume":"183","author":"Leist","year":"2020","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00558","DOI":"10.1128\/msphere.00558-22","article-title":"Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice","volume":"8","author":"Thieulent","year":"2023","journal-title":"mSphere"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kant, R., Kareinen, L., Smura, T., Freitag, T.L., Jha, S.K., Alitalo, K., Meri, S., Sironen, T., Saksela, K., and Strandin, T. (2021). Common Laboratory Mice Are Susceptible to Infection with the SARS-CoV-2 Beta Variant. Viruses, 13.","DOI":"10.21203\/rs.3.rs-762916\/v1"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Metzdorf, K., Jacobsen, H., Greweling-Pils, M.C., Hoffmann, M., L\u00fcddecke, T., Miller, F., Melcher, L., Kempf, A.M., Nehlmeier, I., and Bruder, D. (2023). TMPRSS2 Is Essential for SARS-CoV-2 Beta and Omicron Infection. Viruses, 15.","DOI":"10.3390\/v15020271"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Shuai, H., Chan, J.F.-W., Hu, B., Chai, Y., Yoon, C., Liu, H., Liu, Y., Shi, J., Zhu, T., and Hu, J.-C. (2023). The Viral Fitness and Intrinsic Pathogenicity of Dominant SARS-CoV-2 Omicron Sublineages BA.1, BA.2, and BA.5. eBioMedicine, 95.","DOI":"10.1016\/j.ebiom.2023.104753"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yasui, F., Matsumoto, Y., Yamamoto, N., Sanada, T., Honda, T., Munakata, T., Itoh, Y., and Kohara, M. (2022). Infection with the SARS-CoV-2 B.1.351 Variant Is Lethal in Aged BALB\/c Mice. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-08104-4"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1093\/procel\/pwae007","article-title":"Mutations in the SARS-CoV-2 Spike Receptor Binding Domain and Their Delicate Balance between ACE2 Affinity and Antibody Evasion","volume":"15","author":"Xue","year":"2024","journal-title":"Protein Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/978-1-4939-9732-9_24","article-title":"Immunohistochemistry and In Situ Hybridization in the Developing Chicken Brain","volume":"2047","author":"Tucker","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_36","unstructured":"R Core Team (2019). R: A Language and Environment for Statistical Computing, R Core Team."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/bimj.200810425","article-title":"Simultaneous Inference in General Parametric Models","volume":"50","author":"Hothorn","year":"2008","journal-title":"Biom. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1038\/s41593-021-00926-1","article-title":"The SARS-CoV-2 Main Protease Mpro Causes Microvascular Brain Pathology by Cleaving NEMO in Brain Endothelial Cells","volume":"24","author":"Wenzel","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/s41593-022-01242-y","article-title":"Full Protection from SARS-CoV-2 Brain Infection and Damage in Susceptible Transgenic Mice Conferred by MVA-CoV2-S Vaccine Candidate","volume":"26","author":"Villadiego","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Carossino, M., Kenney, D., O\u2019Connell, A.K., Montanaro, P., Tseng, A.E., Gertje, H.P., Grosz, K.A., Ericsson, M., Huber, B.R., and Kurnick, S.A. (2022). Fatal Neurodissemination and SARS-CoV-2 Tropism in K18-hACE2 Mice Is Only Partially Dependent on hACE2 Expression. Viruses, 14.","DOI":"10.3390\/v14030535"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Liu, H., Brostoff, T., Ramirez, A., Wong, T., Rowland, D.J., Heffner, M., Flores, A., Willis, B., Evans, J.J., and Lanoue, L. (2024). Establishment and Characterization of an hACE2\/hTMPRSS2 Knock-in Mouse Model to Study SARS-CoV-2. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1428711"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.1002\/jmv.27735","article-title":"Comparative Characterization of SARS-CoV-2 Variants of Concern and Mouse-Adapted Strains in Mice","volume":"94","author":"Chen","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Liu, X., Mostafavi, H., Ng, W.H., Freitas, J.R., King, N.J.C., Zaid, A., Taylor, A., and Mahalingam, S. (2022). The Delta SARS-CoV-2 Variant of Concern Induces Distinct Pathogenic Patterns of Respiratory Disease in K18-hACE2 Transgenic Mice Compared to the Ancestral Strain from Wuhan. mBio, 13.","DOI":"10.1128\/mbio.00683-22"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Seehusen, F., Clark, J.J., Sharma, P., Bentley, E.G., Kirby, A., Subramaniam, K., Wunderlin-Giuliani, S., Hughes, G.L., Patterson, E.I., and Michael, B.D. (2022). Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse. Viruses, 14.","DOI":"10.3390\/v14051020"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Stewart, R., Yan, K., Ellis, S.A., Bishop, C.R., Dumenil, T., Tang, B., Nguyen, W., Larcher, T., Parry, R., and Sng, J.D.J. (2023). SARS-CoV-2 Omicron BA.5 and XBB Variants Have Increased Neurotropic Potential over BA.1 in K18-hACE2 Mice and Human Brain Organoids. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1320856"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Natekar, J.P., Pathak, H., Stone, S., Kumari, P., Sharma, S., Auroni, T.T., Arora, K., Rothan, H.A., and Kumar, M. (2022). Differential Pathogenesis of SARS-CoV-2 Variants of Concern in Human ACE2-Expressing Mice. Viruses, 14.","DOI":"10.1101\/2022.04.04.486975"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"100743","DOI":"10.1016\/j.xcrm.2022.100743","article-title":"Virological Features and Pathogenicity of SARS-CoV-2 Omicron BA.2","volume":"3","author":"Chan","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"198563","DOI":"10.1016\/j.virusres.2021.198563","article-title":"Comparison of SARS-CoV-2 Variant Lethality in Human Angiotensin-Converting Enzyme 2 Transgenic Mice","volume":"305","author":"Lee","year":"2021","journal-title":"Virus Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"da Silva Santos, Y., Gamon, T.H.M., de Azevedo, M.S.P., Telezynski, B.L., de Souza, E.E., de Oliveira, D.B.L., Dombrowski, J.G., Rosa-Fernandes, L., Palmisano, G., and de Moura Carvalho, L.J. (2023). Virulence Profiles of Wild-Type, P.1 and Delta SARS-CoV-2 Variants in K18-hACE2 Transgenic Mice. Viruses, 15.","DOI":"10.3390\/v15040999"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/S0140-6736(22)00462-7","article-title":"Comparative Analysis of the Risks of Hospitalisation and Death Associated with SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) Variants in England: A Cohort Study","volume":"399","author":"Nyberg","year":"2022","journal-title":"Lancet"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41586-022-04441-6","article-title":"SARS-CoV-2 Omicron Virus Causes Attenuated Disease in Mice and Hamsters","volume":"603","author":"Halfmann","year":"2022","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41586-022-04442-5","article-title":"Attenuated Replication and Pathogenicity of SARS-CoV-2 B.1.1.529 Omicron","volume":"603","author":"Shuai","year":"2022","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/s41586-022-04474-x","article-title":"Altered TMPRSS2 Usage by SARS-CoV-2 Omicron Impacts Infectivity and Fusogenicity","volume":"603","author":"Meng","year":"2022","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1177\/03009858211043084","article-title":"Cellular Tropism of SARS-CoV-2 in the Respiratory Tract of Syrian Hamsters and B6.Cg-Tg(K18-ACE2)2Prlmn\/J Transgenic Mice","volume":"59","author":"Yen","year":"2022","journal-title":"Vet. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41586-020-2324-7","article-title":"Respiratory Disease in Rhesus Macaques Inoculated with SARS-CoV-2","volume":"585","author":"Munster","year":"2020","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41586-020-2608-y","article-title":"ChAdOx1 nCoV-19 Vaccine Prevents SARS-CoV-2 Pneumonia in Rhesus Macaques","volume":"586","author":"Lambe","year":"2020","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ircmb.2022.01.001","article-title":"Pulmonary Macrophages and SARS-CoV-2 Infection","volume":"367","author":"Bain","year":"2022","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1093\/infdis\/jiab595","article-title":"T-Cell Expression of Angiotensin-Converting Enzyme 2 and Binding of Severe Acute Respiratory Coronavirus 2","volume":"225","author":"Welch","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e0096421","DOI":"10.1128\/JVI.00964-21","article-title":"The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus","volume":"96","author":"Dong","year":"2022","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1753466620933508","DOI":"10.1177\/1753466620933508","article-title":"Lung under Attack by COVID-19-Induced Cytokine Storm: Pathogenic Mechanisms and Therapeutic Implications","volume":"14","author":"Pelaia","year":"2020","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zanza, C., Romenskaya, T., Manetti, A.C., Franceschi, F., La Russa, R., Bertozzi, G., Maiese, A., Savioli, G., Volonnino, G., and Longhitano, Y. (2022). Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina, 58.","DOI":"10.3390\/medicina58020144"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.2174\/138161282822220721121211","article-title":"Cytokine Release Syndrome in Pathogenesis and Treatment of COVID-19","volume":"28","author":"Hu","year":"2022","journal-title":"Curr. Pharm. Des."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2020.06.017","article-title":"Cytokine Storms: Understanding COVID-19","volume":"53","author":"Mangalmurti","year":"2020","journal-title":"Immunity"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cytogfr.2020.06.001","article-title":"SARS-CoV-2 Infection: The Role of Cytokines in COVID-19 Disease","volume":"54","author":"Ruiz","year":"2020","journal-title":"Cytokine Growth Factor. Rev."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/4\/500\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:06:05Z","timestamp":1760029565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/4\/500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,30]]},"references-count":64,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["v17040500"],"URL":"https:\/\/doi.org\/10.3390\/v17040500","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,30]]}}}