(PCT/JP2016/057254; "Method for inducing differentiation of alveolar epithelial cells", PCT/JP2016/059786, "Method of producing airway epithelial cells"). Jumpei Ito has consulting fees and honoraria for lectures from Takeda Pharmaceutical Co. Ltd. Kei Sato has consulting fees from Moderna Japan Co., Ltd. and Takeda Pharmaceutical Co. Ltd. and honoraria for lectures from Gilead Sciences, Inc., Moderna Japan Co., Ltd., and Shionogi & Co., Ltd. The other authors declare that no competing interests exist.

## Acknowledgements

We would like to thank all members belonging to The Genotype to Phenotype Japan (G2P-Japan) Consortium. We thank Dr. Kenzo Tokunaga (National Institute for Infectious Diseases, Japan) and Dr. Yuh-Pyng Sher (Graduate Institute of Biomedical Sciences, China Medical University, China) for providing reagents. We gratefully acknowledge all data contributors, i.e., the Authors and their Originating laboratories responsible for obtaining the specimens, and their Submitting laboratories for generating the genetic sequence and metadata and sharing via the GISAID Initiative, on which this research is based. The supercomputing resource was provided by Human Genome Center at The University of Tokyo. This study was supported in part by AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVREd) (JP223fa627005, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation

(to Tomokazu Tamura); and The Naito Foundation (to Terumasa Ikeda); Mitsubishi Foundation (to Kei Sato).

## Consortia:

The Genotype to Phenotype Japan (G2P-Japan) Consortium.

Hirofumi Sawa³¹, Keita Mizuma¹³, Jingshu Li¹³, Yume Mimura¹³, Yuma Ohari¹³, Tomoya Tsubo³¹, Zannatul Ferdous⁸, Kenji Shishido⁸, Hiromi Mohri⁸, Miki Iida⁸, Shuhei Tsujino⁴, Naoko Misawa¹, Kaoru Usui¹, Wilaiporn Saikruang¹, Spyridon Lytras¹, Shusuke Kawakubo¹, Luca Nishumura¹, Jarel Elgin M. Tolentino¹, Wenye Li¹, Maximilian S. Yo¹, Kio Horinaka¹, Mai Sugarani¹, Mika Chiba¹, Ryo Yoshimura¹, Kyoko Yasuda¹, Keiko Iida¹, Adam P. Strange¹, Naomi Ohsumi¹, Shiro Tanaka¹, Eiko Ogawa¹, Kaho Okumura¹, Tsuki Fukuda¹, Rina Osujo¹, Isao Yoshida²¹, So Nakagawa³², Akifumi Takaori-Kondo³³, Kotaro Shirakawa³³, Kayoko Nagata³³, Ryosuke Nomura³³, Yoshihito Horisawa³³, Yusuke Tashiro³³, Yugo Kawai³³, Yoshitaka Nakata³, Hiroki Futatsusako³, Ayaka Sakamoto³, Naoko Yasuhara³, Takao Hashiguchi³³, Tateki Suzuki³³, Kanako Kimura³³, Jiei Sasaki³³, Yukari Nakajima³³, Hisano Yajima³³, Takashi Irie³⁴, Ryoko Kawabata³⁴, Kaori Sasaki-Tabata³⁵, Ryo Shimizu¹⁰, MST Monira Begum¹⁰, Michael Jonathan¹⁰, Yuka Mugita¹⁰, Sharee Leong¹⁰, Otowa Takahashi¹⁰, Kimiko Ichihara¹⁰, Takamasa Ueno³⁶, Chihiro Motozono³⁶, Mako Toyoda³⁶, Akatsuki Saito³⁷, Anon Kosaka³⁷, Miki Kawano³⁷, Natsumi Matsubara³⁷, Tomoko Nishiuchi³⁷, Jiri Zahradnik³⁸, Prokopios Andrikopoulos³⁸, Miguel Padilla-Blanco³⁸, Aditi Konar³⁸

³³ Hokkaido University, Sapporo, Japan.

³² Tokai University School of Medicine, Isehara, Japan.

³³ Kyoto University, Kyoto, Japan.

³⁴ Hiroshima University, Hiroshima, Japan.

³⁵ Kyushu University, Fukuoka, Japan.

³⁶ Kumamoto University, Kumamoto, Japan.

³⁷ Miyazaki University, Miyazaki, Japan.

³⁸ Charles University, Vestec-Prague, Czechia.

## Appendix A. Supplementary data

Supplementary data related to this article can be found at https://doi.org/10.1016/j.ebiom.2024.105181.

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24 Wickenhagen A, Sugrue E, Lytras S, et al. A prenylated dsRNA sensor protects against severe COVID-19. *Science*. 2021;374(6567):eabj3624.

25 Xu F, Wang G, Zhao F, et al. IFITM3 inhibits SARS-CoV-2 infection and is associated with COVID-19 susceptibility. *Viruses*. 2022;14(11).

26 Mar KB, Wells AI, Caballero Van Dyke MC, et al. LY6E is a coronavirus restriction factor in the respiratory tract. *Nat Microbiol.* 2023;8(8):1587–1599.

27 Xu D, Jiang W, Wu L, et al. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. *Nature*. 2023;619(7971):819–827.

28 Steiner S, Kratzel A, Barut GT, et al. SARS-CoV-2 biology and host interactions. *Nat Rev Microbiol.* 2024;22(4):206–225.

29 Sano E, Suzuki T, Hashimoto R, et al. Cell response analysis in SARS-CoV-2 infected bronchial organoids. *Commun Biol.* 2022;5(1):516.

30 Tamura T, Ito J, Uriu K, et al. Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants. *Nat Commun.* 2023;14(1):2800.

31 Kimura I, Yamasoba D, Tamura T, et al. Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.4 and BA.5. *Cell.* 2022;185(21):3992–4007.e16.

32 Yamamoto Y, Gotoh S, Korogi Y, et al. Long-term expansion of alveolar stem cells derived from human iPS cells in organoids. *Nat Methods.* 2017;14(11):1097–1106.

33 Konishi S, Gotoh S, Tateishi K, et al. Directed induction of functional multi-ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells. *Stem Cell Rep.* 2016;6(1):18–25.

34 Gotoh S, Ito I, Nagasaki T, et al. Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells. *Stem Cell Rep.* 2014;3(3):394–403.

35 Fujita S, Kosugi Y, Kimura I, et al. Determination of the factors responsible for the tropism of SARS-CoV-2-related bat coronaviruses to Rhinolophus bat ACE2. *J Virol.* 2023:e0099023.

36 Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. *Gene.* 1991;108(2):193–199.

37 Suzuki R, Yamasoba D, Kimura I, et al. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant. *Nature.* 2022;603(7902):700–705.

38 Saito A, Irie T, Suzuki R, et al. Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. *Nature.* 2022;602(7896):300–306.

39 Torii S, Ono C, Suzuki R, et al. Establishment of a reverse genetics system for SARS-CoV-2 using circular polymerase extension reaction. *Cell Rep.* 2021;35(3):109014.

40 Yamasoba D, Kimura I, Nasser H, et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. *Cell.* 2022;185(12):2103–2115.e19.

41 Kimura I, Yamasoba D, Nasser H, et al. The SARS-CoV-2 spike S375F mutation characterizes the Omicron BA.1 variant. *iScience.* 2022;25(12):105720.

42 Meng B, Abdullahi A, Ferreira IATM, et al. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. *Nature.* 2022;603(7902):706–714.

43 Miyamoto S, Arashiro T, Adachi Y, et al. Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants. *Med.* 2022;3(4):249–261 e4.

44 Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. *Am J Hygiene.* 1938;27:493–497.

45 Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. *Bioinformatics.* 2018;34(17):i884–i890.

46 Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. *Bioinformatics.* 2009;25(14):1754–1760.

47 Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. *Bioinformatics.* 2009;25(16):2078–2079.

48 Cingolani P, Platts A, Wang le L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118: iso-2; iso-3. *Fly (Austin).* 2012;6(2):80–92.

49 Deguchi S, Tsuda M, Kosugi K, et al. Usability of polydimethylsiloxane-based microfluidic devices in pharmaceutical research using human hepatocytes. *ACS Biomater Sci Eng.* 2021;7(8):3648–3657.

50 Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. *Bioinformatics.* 2013;29(1):15–21.

51 Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. *Bioinformatics.* 2014;30(7):923–930.

52 R Core Team. *R: a language and environment for statistical computing*. Vienna, Austria: R Foundation for Statistical Computing; 2023. https://www.R-project.org/.

53 Hart T, Komori HK, LaMere S, Podshivalova K, Salomon DR. Finding the active genes in deep RNA-seq gene expression studies. *BMC Genom.* 2013;14:778.

54 Ammar R, Thompson J. *zFPKM: a suite of functions to facilitate zFPKM transformations*. R package v1.22.0; 2023. https://github.com/ronammar/zFPKM/.

55 Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. *Genome Biol.* 2014;15(12):550.

56 Zhu A, Ibrahim JG, Love MI. Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. *Bioinformatics.* 2019;35(12):2084–2092.

57 Blighe K, Lun A. *PCAtools: everything principal components analysis*. R package v2.12.0; 2023. https://github.com/kevinblighe/PCAtools.

58 Brown GR, Hem V, Katz KS, et al. Gene: a gene-centered information resource at NCBI. *Nucleic Acids Res.* 2015;43(D1):D36–D42.

59 Domaszewska T, Scheuermann L, Hahnke K, et al. Concordant and discordant gene expression patterns in mouse strains identify best-fit animal model for human tuberculosis. *Sci Rep.* 2017;7(1):12094.

60 Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. *Innovation.* 2021;2(3):100141.

61 Nasser H, Shimizu R, Ito J, et al. Monitoring fusion kinetics of viral and target cell membranes in living cells using a SARS-CoV-2 spike-protein-mediated membrane fusion assay. *STAR Protoc.* 2022;3(4):101773.

62 Begum MM, Ichihara K, Takahashi O, et al. Virological characteristics correlating with SARS-CoV-2 spike protein fusogenicity. *Front Virol.* 2024;4.

63 Kondo N, Miyauchi K, Matsuda Z. Monitoring viral-mediated membrane fusion using fluorescent reporter methods. *Curr Protox Cell Biol.* 2011;26. Unit 26 9.
origins of SARS-CoV and SARS-CoV-2. *Res Sq.* 2023. https://doi.org/10.21203/rs.3.rs-3227228/v1.

13 Johnson BA, Xie X, Bailey AL, et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. *Nature*. 2021;591(7849):293–299.

14 Peacock TP, Goldhill DH, Zhou J, et al. The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets. *Nat Microbiol.* 2021;6(7):899–909.

15 Temmam S, Vongphayloth K, Baquero E, et al. Bat coronaviruses related to SARS-CoV-2 and infectious for human cells. *Nature*. 2022;604(7905):330–336.

16 Ozono S, Zhang Y, Ode H, et al. SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. *Nat Commun.* 2021;12(1):848.

17 Ferreira I, Kemp SA, Datir R, et al. SARS-CoV-2 B.1.617 mutations L452R and E484Q are not synergistic for antibody evasion. *J Infect Dis.* 2021;224(6):989–994.

18 Motozono C, Toyoda M, Zahradnik J, et al. SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity. *Cell Host Microbe.* 2021;29(7):1124–1136.

19 Matsuyama S, Nao N, Shirato K, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. *Proc Natl Acad Sci U S A.* 2020;117(13):7001–7003.

20 Ito J, Suzuki R, Uriu K, et al. Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant. *Nat Commun.* 2023;14(1):2671.

21 Saito A, Tamura T, Zahradnik J, et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant. *Cell Host Microbe.* 2022;30(11):1540–1555.e15.

22 Hashimoto R, Takahashi J, Shirakura K, et al. SARS-CoV-2 disrupts the respiratory vascular barrier by suppressing Claudin-5 expression. *Sci Adv.* 2022;8(38):eab06783.

23 Tamura T, Yamasoba D, Oda Y, et al. Comparative pathogenicity of SARS-CoV-2 Omicron subvariants including BA.1, BA.2, and BA.5. *Commun Biol.* 2023;6(1):772.

24 Wickenhagen A, Sugrue E, Lytras S, et al. A prenylated dsRNA sensor protects against severe COVID-19. *Science*. 2021;374(6567):eab3624.

25 Xu F, Wang G, Zhao F, et al. IFITM3 inhibits SARS-CoV-2 infection and is associated with COVID-19 susceptibility. *Viruses*. 2022;14(11).

26 Mar KB, Wells AI, Caballero Van Dyke MC, et al. LY6E is a coronavirus restriction factor in the respiratory tract. *Nat Microbiol.* 2023;8(8):1587–1599.

27 Xu D, Jiang W, Wu L, et al. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. *Nature*. 2023;619(7971):819–827.

28 Steiner S, Kratzel A, Barut GT, et al. SARS-CoV-2 biology and host interactions. *Nat Rev Microbiol.* 2024;22(4):206–225.

29 Sano E, Suzuki T, Hashimoto R, et al. Cell response analysis in SARS-CoV-2 infected bronchial organoids. *Commun Biol.* 2022;5(1):516.

30 Tamura T, Ito J, Uriu K, et al. Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants. *Nat Commun.* 2023;14(1):2800.

31 Kimura I, Yamasoba D, Tamura T, et al. Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.4 and BA.5. *Cell.* 2022;185(21):3992–4007.e16.

32 Yamamoto Y, Gotoh S, Korogi Y, et al. Long-term expansion of alveolar stem cells derived from human iPS cells in organoids. *Nat Methods.* 2017;14(11):1097–1106.

33 Konishi S, Gotoh S, Tateishi K, et al. Directed induction of functional multi-ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells. *Stem Cell Rep.* 2016;6(1):18–25.

34 Gotoh S, Ito I, Nagasaki T, et al. Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells. *Stem Cell Rep.* 2014;3(3):394–403.

35 Fujita S, Kosugi Y, Kimura I, et al. Determination of the factors responsible for the tropism of SARS-CoV-2-related bat coronaviruses to Rhinolophus bat ACE2. *J Virol.* 2023:e0099023.

36 Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. *Gene.* 1991;108(2):193–199.

37 Suzuki R, Yamasoba D, Kimura I, et al. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant. *Nature.* 2022;603(7902):700–705.

38 Saito A, Irie T, Suzuki R, et al. Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. *Nature*. 2022;602(7896):300–306.

39 Torii S, Ono C, Suzuki R, et al. Establishment of a reverse genetics system for SARS-CoV-2 using circular polymerase extension reaction. *Cell Rep.* 2021;35(3):109014.

40 Yamasoba D, Kimura I, Nasser H, et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. *Cell.* 2022;185(12):2103–2115.e19.

41 Kimura I, Yamasoba D, Nasser H, et al. The SARS-CoV-2 spike S375F mutation characterizes the Omicron BA.1 variant. *iScience.* 2022;25(12):105720.

42 Meng B, Abdullahi A, Ferreira IATM, et al. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. *Nature.* 2022;603(7902):706–714.

43 Miyamoto S, Arashiro T, Adachi Y, et al. Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants. *Med.* 2022;3(4):249–261 e4.

44 Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. *Am J Hygiene.* 1938;27:493–497.

45 Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. *Bioinformatics.* 2018;34(17):i884–i890.

46 Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. *Bioinformatics.* 2009;25(14):1754–1760.

47 Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. *Bioinformatics.* 2009;25(16):2078–2079.

48 Cingolani P, Platts A, Wang le L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118: iso-2; iso-3. *Fly (Austin).* 2012;6(2):80–92.

49 Deguchi S, Tsuda M, Kosugi K, et al. Usability of polydimethylsiloxane-based microfluidic devices in pharmaceutical research using human hepatocytes. *ACS Biomater Sci Eng.* 2021;7(8):3648–3657.

50 Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. *Bioinformatics.* 2013;29(1):15–21.

51 Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. *Bioinformatics.* 2014;30(7):923–930.

52 R Core Team. *R: a language and environment for statistical computing*. Vienna, Austria: R Foundation for Statistical Computing; 2023. https://www.R-project.org/.

53 Hart T, Komori HK, LaMere S, Podshivalova K, Salomon DR. Finding the active genes in deep RNA-seq gene expression studies. *BMC Genom.* 2013;14:778.

54 Ammar R, Thompson J. *zFPKM: a suite of functions to facilitate zFPKM transformations*. R package v1.22.0; 2023. https://github.com/ronammar/zFPKM/.

55 Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. *Genome Biol.* 2014;15(12):550.

56 Zhu A, Ibrahim JG, Love MI. Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. *Bioinformatics.* 2019;35(12):2084–2092.

57 Blighe K, Lun A. *PCAtools: everything principal components analysis*. R package v2.12.0; 2023. https://github.com/kevinblighe/PCAtools.

58 Brown GR, Hem V, Katz KS, et al. Gene: a gene-centered information resource at NCBI. *Nucleic Acids Res.* 2015;43(D1):D36–D42.

59 Domaszewska T, Scheuermann L, Hahnke K, et al. Concordant and discordant gene expression patterns in mouse strains identify best-fit animal model for human tuberculosis. *Sci Rep.* 2017;7(1):12094.

60 Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. *Innovation.* 2021;2(3):100141.

61 Nasser H, Shimizu R, Ito J, et al. Monitoring fusion kinetics of viral and target cell membranes in living cells using a SARS-CoV-2 spike-protein-mediated membrane fusion assay. *STAR Protoc.* 2022;3(4):101773.

62 Begum MM, Ichihara K, Takahashi O, et al. Virological characteristics correlating with SARS-CoV-2 spike protein fusogenicity. *Front Virol.* 2024;4.

63 Kondo N, Miyauchi K, Matsuda Z. Monitoring viral-mediated membrane fusion using fluorescent reporter methods. *Curr Protox Cell Biol.* 2011;26. Unit 26 9.
64 Uriu K, Kimura I, Shirakawa K, et al. Neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine serum. *N Engl J Med*. 2021;385(25):2397-2399.

65 Uriu K, Cardenas P, Munoz E, et al. Characterization of the immune resistance of SARS-CoV-2 Mu variant and the robust immunity induced by Mu infection. *J Infect Dis*. 2022.

66 Fujita S, Kosugi Y, Kimura I, Yamasoba D, The Genotype To Phenotype Japan GPJC, Sato K. Structural insight into the resistance of the SARS-CoV-2 omicron BA.4 and BA.5 variants to cilgavimab. *Viruses*. 2022;14(12).

67 Kimura I, Kosugi Y, Wu J, et al. The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance. *Cell Rep*. 2022;38(2):110218.

68 Yamasoba D, Kosugi Y, Kimura I, et al. Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies. *Lancet Infect Dis*. 2022;22(7):942-943.

69 Chan JF, Huang X, Hu B, et al. Altered host protease determinants for SARS-CoV-2 Omicron. *Sci Adv*. 2023;9(3):eadd3867.

70 Lin CY, Cho CF, Bai ST, et al. ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT. *Sci Rep*. 2017;7(1):15108.

71 Kassambara A. r. *statix*: pipe-friendly framework for basic statistical tests. R package v0.7.2; 2023. https://CRAN.R-project.org/package=rstatix.

72 Watanabe Y, Kimura I, Hashimoto R, et al. Virological characterization of the 2022 outbreak-causing monkeypox virus using human keratinocytes and colon organoids. *J Med Virol*. 2023;95(6):e28827.

73 Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. *Cell*. 2020;181(2):271-280 e8.

74 Zhao MM, Yang WL, Yang FY, et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. *Signal Transduct Target Ther*. 2021;6(1):134.

75 Cantuti-Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. *Science*. 2020;370(6518):856-860.

76 Baggen J, Jacquemyn M, Persoons L, et al. TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. *Cell*. 2023;186(16):3427-3442 e22.

77 Lam TT, Jia N, Zhang YW, et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. *Nature*. 2020;583(7815):282-285.

78 Liu MQ, Lin HF, Li J, et al. A SARS-CoV-2-related virus from malayan pangolin causes lung infection without severe disease in human ACE2-transgenic mice. *J Virol*. 2023;97(2):e0171922.

79 Temmam S, Montagutelli X, Herate C, et al. SARS-CoV-2-related bat virus behavior in human-relevant models sheds light on the origin of COVID-19. *EMBO Rep*. 2023;24(4):e56055.
64 Uriu K, Kimura I, Shirakawa K, et al. Neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine serum. *N Engl J Med*. 2021;385(25):2397-2399.

65 Uriu K, Cardenas P, Munoz E, et al. Characterization of the immune resistance of SARS-CoV-2 Mu variant and the robust immunity induced by Mu infection. *J Infect Dis*. 2022.

66 Fujita S, Kosugi Y, Kimura I, Yamasoba D, The Genotype To Phenotype Japan GPJC, Sato K. Structural insight into the resistance of the SARS-CoV-2 omicron BA.4 and BA.5 variants to cilgavimab. *Viruses*. 2022;14(12).

67 Kimura I, Kosugi Y, Wu J, et al. The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance. *Cell Rep*. 2022;38(2):110218.

68 Yamasoba D, Kosugi Y, Kimura I, et al. Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies. *Lancet Infect Dis*. 2022;22(7):942-943.

69 Chan JF, Huang X, Hu B, et al. Altered host protease determinants for SARS-CoV-2 Omicron. *Sci Adv*. 2023;9(3):eadd3867.

70 Lin CY, Cho CF, Bai ST, et al. ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT. *Sci Rep*. 2017;7(1):15108.

71 Kassambara A. r. *statix*: pipe-friendly framework for basic statistical tests. R package v0.7.2; 2023. https://CRAN.R-project.org/package=rstatix.

72 Watanabe Y, Kimura I, Hashimoto R, et al. Virological characterization of the 2022 outbreak-causing monkeypox virus using human keratinocytes and colon organoids. *J Med Virol*. 2023;95(6):e28827.

73 Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. *Cell*. 2020;181(2):271-280 e8.

74 Zhao MM, Yang WL, Yang FY, et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. *Signal Transduct Target Ther*. 2021;6(1):134.

75 Cantuti-Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. *Science*. 2020;370(6518):856-860.

76 Baggen J, Jacquemyn M, Persoons L, et al. TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. *Cell*. 2023;186(16):3427-3442 e22.

77 Lam TT, Jia N, Zhang YW, et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. *Nature*. 2020;583(7815):282-285.

78 Liu MQ, Lin HF, Li J, et al. A SARS-CoV-2-related virus from malayan pangolin causes lung infection without severe disease in human ACE2-transgenic mice. *J Virol*. 2023;97(2):e0171922.

79 Temmam S, Montagutelli X, Herate C, et al. SARS-CoV-2-related bat virus behavior in human-relevant models sheds light on the origin of COVID-19. *EMBO Rep*. 2023;24(4):e56055.