{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T08:41:37Z","timestamp":1778056897780,"version":"3.51.4"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,8,3]],"date-time":"2015-08-03T00:00:00Z","timestamp":1438560000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,8,3]],"date-time":"2015-08-03T00:00:00Z","timestamp":1438560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Due to the increasing concern of using smallpox virus as biological weapons for terrorist attack, there is renewed interest in studying the pathogenesis of human smallpox and development of new therapies. Animal models are highly demanded for efficacy and safety examination of new vaccines and therapeutic drugs. Here, we demonstrated that both wild type and immunodeficient rats infected with an engineered vaccinia virus carrying Firefly luciferase reporter gene (rTV-Fluc) could recapitulate infectious and clinical features of human smallpox. Vaccinia viral infection in wild type Sprague-Dawley (SD) rats displayed a diffusible pattern in various organs, including liver, head and limbs. The intensity of bioluminescence generated from rTV-Fluc correlated well with viral loads in tissues. Moreover, neutralizing antibodies had a protective effect against virus reinfection. The recombination activating gene 2 (Rag2) knockout rats generated by transcription activator-like effector nucleases (TALENs) technology were further used to examine the infectivity of the rTV-Fluc in immunodeficient populations. Here we demonstrated that Rag2-\/- rats were more susceptible to rTV-Fluc than SD rats with a slower virus clearance rate. Therefore, the rTV-Fluc\/SD rats and rTV-Fluc\/Rag2-\/- rats are suitable visualization models, which recapitulate wild type or immunodeficient populations respectively, for testing human smallpox vaccine and antiviral drugs.<\/jats:p>","DOI":"10.1038\/srep11397","type":"journal-article","created":{"date-parts":[[2015,8,3]],"date-time":"2015-08-03T10:23:07Z","timestamp":1438597387000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Bioluminescent imaging of vaccinia virus infection in immunocompetent and immunodeficient rats as a model for human smallpox"],"prefix":"10.1038","volume":"5","author":[{"given":"Qiang","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changfa","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuya","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexu","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaoshe","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuelei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weijin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baowen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengming","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youchun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,3]]},"reference":[{"key":"BFsrep11397_CR1","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/509022a","volume":"509","author":"S Reardon","year":"2014","unstructured":"Reardon, S. Infectious diseases: Smallpox watch. Nature. 509, 22\u201324 (2014).","journal-title":"Nature"},{"key":"BFsrep11397_CR2","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/S0140-6736(06)68143-9","volume":"367","author":"ZS Moore","year":"2006","unstructured":"Moore, Z. S., Seward J. F. & Lane J. M. Smallpox. The Lancet. 367, 425\u2013435 (2006).","journal-title":"The Lancet"},{"key":"BFsrep11397_CR3","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1586\/14787210.2014.979157","volume":"12","author":"I Arita","year":"2014","unstructured":"Arita, I. Discovery of forgotten variola specimens at the National Institutes of Health in the USA. Expert Rev. Anti. Infect. Ther. 12, 1419\u20131421 (2014).","journal-title":"Expert Rev. Anti. Infect. Ther"},{"key":"BFsrep11397_CR4","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1126\/science.296.5576.2116","volume":"296","author":"M Enserink","year":"2002","unstructured":"Enserink, M. Biowarfare. Did bioweapons test cause a deadly smallpox outbreak? Science. 296, 2116\u20132117 (2002).","journal-title":"Science"},{"key":"BFsrep11397_CR5","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/S0140-6736(05)70209-9","volume":"365","author":"GA Poland","year":"2005","unstructured":"Poland, G. A. Smallpox vaccines: from first to second to third generation. The Lancet. 365, 362\u2013363 (2005).","journal-title":"The Lancet"},{"key":"BFsrep11397_CR6","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1128\/CVI.00040-09","volume":"16","author":"CA Meseda","year":"2009","unstructured":"Meseda, C. A. et al. Comparative evaluation of the immune responses and protection engendered by LC16m8 and Dryvax smallpox vaccines in a mouse model. Clin. Vaccine Immunol. 16, 1261\u20131271 (2009).","journal-title":"Clin. Vaccine Immunol."},{"key":"BFsrep11397_CR7","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1016\/j.vaccine.2006.10.009","volume":"25","author":"Y Xiao","year":"2007","unstructured":"Xiao, Y. et al. A protein-based smallpox vaccine protects mice from vaccinia and ectromelia virus challenges when given as a prime and single boost. Vaccine. 25, 1214\u20131224 (2007).","journal-title":"Vaccine."},{"key":"BFsrep11397_CR8","doi-asserted-by":"publisher","first-page":"11084","DOI":"10.1128\/JVI.00423-07","volume":"81","author":"MM Adams","year":"2007","unstructured":"Adams, M. M., Rice A. D. & Moyer R. W. Rabbitpox virus and vaccinia virus infection of rabbits as a model for human smallpox. J. Virol. 81, 11084\u201311095 (2007).","journal-title":"J. Virol."},{"key":"BFsrep11397_CR9","doi-asserted-by":"publisher","first-page":"5179","DOI":"10.1128\/JVI.02642-05","volume":"80","author":"M Saijo","year":"2006","unstructured":"Saijo, M. et al. LC16m8, a highly attenuated vaccinia virus vaccine lacking expression of the membrane protein B5R, protects monkeys from monkeypox. J. Virol. 80, 5179\u20135188 (2006).","journal-title":"J. Virol."},{"key":"BFsrep11397_CR10","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nature02426","volume":"428","author":"RA Gibbs","year":"2004","unstructured":"Gibbs, R. A. et al. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 428, 493\u2013521 (2004).","journal-title":"Nature"},{"key":"BFsrep11397_CR11","doi-asserted-by":"publisher","first-page":"437","DOI":"10.2174\/187152611797636686","volume":"11","author":"MY Russell","year":"2011","unstructured":"Russell, M. Y., Palmer A. & Michaels M. G. Cytomegalovirus infection in pediatric immunocompromised hosts. Infect. Disord. Drug Targets. 11, 437\u2013448 (2011).","journal-title":"Infect. Disord. Drug Targets"},{"key":"BFsrep11397_CR12","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S1045-1870(03)00032-3","volume":"14","author":"JM Lane","year":"2003","unstructured":"Lane, J. M. & Goldstein J. Adverse events occurring after smallpox vaccination. Semin. Pediatr. Infect. Dis. 14, 189\u2013195 (2003).","journal-title":"Semin. Pediatr. Infect. Dis."},{"key":"BFsrep11397_CR13","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1073\/pnas.0912134107","volume":"107","author":"DW Grosenbach","year":"2010","unstructured":"Grosenbach, D. W. et al. Efficacy of ST-246 versus lethal poxvirus challenge in immunodeficient mice. Proc. Natl. Acad. Sci. USA. 107, 838\u2013843 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep11397_CR14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1128\/mr.55.1.80-122.1991","volume":"55","author":"RM Buller","year":"1991","unstructured":"Buller, R. M. & Palumbo G. J. Poxvirus pathogenesis. Microbiol. Rev. 55, 80\u2013122 (1991).","journal-title":"Microbiol. Rev."},{"key":"BFsrep11397_CR15","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1586\/14787210.4.2.277","volume":"4","author":"R Jordan","year":"2006","unstructured":"Jordan, R. & Hruby D. Smallpox antiviral drug development: satisfying the animal efficacy rule. Expert. Rev. Anti. Infect. Ther. 4, 277\u2013289 (2006).","journal-title":"Expert. Rev. Anti. Infect. Ther"},{"key":"BFsrep11397_CR16","doi-asserted-by":"publisher","first-page":"e33392","DOI":"10.1371\/journal.pone.0033392","volume":"7","author":"Q Liu","year":"2012","unstructured":"Liu, Q. et al. A novel high-throughput vaccinia virus neutralization assay and preexisting immunity in populations from different geographic regions in China. PLoS One. 7, e33392 (2012).","journal-title":"PLoS One."},{"key":"BFsrep11397_CR17","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.1007\/s00705-014-2079-2","volume":"159","author":"R Zhu","year":"2014","unstructured":"Zhu, R., Liu Q., Huang W., Yu Y. & Wang Y. Comparison of the replication characteristics of vaccinia virus strains Guang 9 and Tian Tan in vivo and in vitro. Arch. Virol. 159, 2587\u20132596 (2014).","journal-title":"Arch. Virol."},{"key":"BFsrep11397_CR18","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.virol.2005.06.049","volume":"341","author":"KE Luker","year":"2005","unstructured":"Luker, K. E., Hutchens M., Schultz T., Pekosz A. & Luker G. D. Bioluminescence imaging of vaccinia virus: effects of interferon on viral replication and spread. Virology. 341, 284\u2013300 (2005).","journal-title":"Virology."},{"key":"BFsrep11397_CR19","doi-asserted-by":"publisher","first-page":"10437","DOI":"10.1128\/JVI.01296-09","volume":"83","author":"M Zaitseva","year":"2009","unstructured":"Zaitseva, M. et al. Application of bioluminescence imaging to the prediction of lethality in vaccinia virus-infected mice. J. Virol. 83, 10437\u201310447 (2009).","journal-title":"J. Virol."},{"key":"BFsrep11397_CR20","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/nature09368","volume":"467","author":"C Tong","year":"2010","unstructured":"Tong, C., Li P., Wu N. L., Yan Y. & Ying Q. L. Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. Nature. 467, 211\u2013213 (2010).","journal-title":"Nature."},{"key":"BFsrep11397_CR21","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/nbt.1940","volume":"29","author":"L Tesson","year":"2011","unstructured":"Tesson, L. et al. Knockout rats generated by embryo microinjection of TALENs. Nat. Biotechnol. 29, 695\u2013696 (2011).","journal-title":"Nat. Biotechnol."},{"key":"BFsrep11397_CR22","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1038\/nbt.2652","volume":"31","author":"W Li","year":"2013","unstructured":"Li, W., Teng F., Li T. & Zhou Q. Simultaneous generation and germline transmission of multiple gene mutations in rat using CRISPR-Cas systems. Nat. Biotechnol. 31, 684\u2013686 (2013).","journal-title":"Nat. Biotechnol."},{"key":"BFsrep11397_CR23","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1002\/bit.24890","volume":"110","author":"N Sun","year":"2013","unstructured":"Sun, N. & Zhao H. Transcription activator-like effector nucleases (TALENs): a highly efficient and versatile tool for genome editing. Biotechnol. Bioeng. 110, 1811\u20131821 (2013).","journal-title":"Biotechnol. Bioeng."},{"key":"BFsrep11397_CR24","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1111\/j.1462-5822.2007.00995.x","volume":"9","author":"M Hutchens","year":"2007","unstructured":"Hutchens, M. & Luker G. D. Applications of bioluminescence imaging to the study of infectious diseases. Cell Microbiol. 9, 2315\u20132322 (2007).","journal-title":"Cell Microbiol."},{"key":"BFsrep11397_CR25","doi-asserted-by":"publisher","first-page":"4898","DOI":"10.1128\/JVI.02525-10","volume":"85","author":"AJ Goff","year":"2011","unstructured":"Goff, A. J. et al. A novel respiratory model of infection with monkeypox virus in cynomolgus macaques. J. Virol. 85, 4898\u20134909 (2011).","journal-title":"J. Virol."},{"key":"BFsrep11397_CR26","doi-asserted-by":"publisher","first-page":"e6592","DOI":"10.1371\/journal.pone.0006592","volume":"4","author":"JE Osorio","year":"2009","unstructured":"Osorio, J. E., Iams K. P., Meteyer C. U. & Rocke T. E. Comparison of monkeypox viruses pathogenesis in mice by in vivo imaging. PLoS One. 4, e6592 (2009).","journal-title":"PLoS One."},{"key":"BFsrep11397_CR27","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1067\/mai.2002.128052","volume":"110","author":"RJ Engler","year":"2002","unstructured":"Engler, R. J., Kenner J. & Leung D. Y. Smallpox vaccination: Risk considerations for patients with atopic dermatitis. J. Allergy Clin. Immunol. 110, 357\u2013365 (2002).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep11397_CR28","doi-asserted-by":"publisher","first-page":"6265","DOI":"10.4049\/jimmunol.172.10.6265","volume":"172","author":"R Xu","year":"2004","unstructured":"Xu, R., Johnson A. J., Liggitt D. & Bevan M. J. Cellular and humoral immunity against vaccinia virus infection of mice. J. Immunol. 172, 6265\u20136271 (2004).","journal-title":"J. Immunol."},{"key":"BFsrep11397_CR29","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.vaccine.2009.09.086","volume":"28","author":"JE Moyron-Quiroz","year":"2009","unstructured":"Moyron-Quiroz, J. E., McCausland M. M., Kageyama R., Sette A. & Crotty S. The smallpox vaccine induces an early neutralizing IgM response. Vaccine. 28, 140\u2013147 (2009).","journal-title":"Vaccine."},{"key":"BFsrep11397_CR30","doi-asserted-by":"publisher","first-page":"6333","DOI":"10.1128\/JVI.00115-06","volume":"80","author":"V Panchanathan","year":"2006","unstructured":"Panchanathan, V., Chaudhri G. & Karupiah G. Protective immunity against secondary poxvirus infection is dependent on antibody but not on CD4 or CD8 T-cell function. J. Virol. 80, 6333\u20136338 (2006).","journal-title":"J. Virol."},{"key":"BFsrep11397_CR31","doi-asserted-by":"publisher","first-page":"4590","DOI":"10.1073\/pnas.0401165101","volume":"101","author":"LS Wyatt","year":"2004","unstructured":"Wyatt, L. S., Earl P. L., Eller L. A. & Moss B. Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proc. Natl. Acad. Sci. USA. 101, 4590\u20134595 (2004).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep11397_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.antiviral.2009.06.006","volume":"84","author":"BL Jacobs","year":"2009","unstructured":"Jacobs, B. L. et al. Vaccinia virus vaccines: past, present and future. Antiviral Res. 84, 1\u201313 (2009).","journal-title":"Antiviral Res."},{"key":"BFsrep11397_CR33","doi-asserted-by":"publisher","first-page":"9983","DOI":"10.1073\/pnas.1202143109","volume":"109","author":"M Fang","year":"2012","unstructured":"Fang, M. et al. Perforin-dependent CD4+ T-cell cytotoxicity contributes to control a murine poxvirus infection. Proc. Natl. Acad. Sci. USA. 109, 9983\u20139988 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep11397_CR34","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1128\/CVI.00280-10","volume":"18","author":"RW Fisher","year":"2011","unstructured":"Fisher, R. W. et al. Postexposure prevention of progressive vaccinia in SCID mice treated with vaccinia immune globulin. Clin. Vaccine Immunol. 18, 67\u201374 (2011).","journal-title":"Clin. Vaccine Immunol."},{"key":"BFsrep11397_CR35","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/317813a0","volume":"317","author":"RM Buller","year":"1985","unstructured":"Buller, R. M., Smith G. L., Cremer K., Notkins A. L. & Moss B. Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative phenotype. Nature. 317, 813\u2013815 (1985).","journal-title":"Nature."},{"key":"BFsrep11397_CR36","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1099\/0022-1317-81-2-431","volume":"81","author":"BE Coupar","year":"2000","unstructured":"Coupar, B. E., Oke P. G. & Andrew M. E. Insertion sites for recombinant vaccinia virus construction: effects on expression of a foreign protein. J. Gen. Virol. 81, 431\u2013439 (2000).","journal-title":"J. Gen. Virol."},{"key":"BFsrep11397_CR37","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.jviromet.2007.03.012","volume":"144","author":"W Zhu","year":"2007","unstructured":"Zhu, W. et al. The attenuation of vaccinia Tian Tan strain by the removal of the viral M1L-K2L genes. J. Virol. Methods. 144, 17\u201326 (2007).","journal-title":"J. Virol. Methods."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep11397","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep11397.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep11397.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T17:53:05Z","timestamp":1672941185000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep11397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,3]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,9,1]]}},"alternative-id":["BFsrep11397"],"URL":"https:\/\/doi.org\/10.1038\/srep11397","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,3]]},"assertion":[{"value":"3 December 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 May 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11397"}}