{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:27:31Z","timestamp":1768292851855,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIAID Emerging and Tropical Infectious Diseases Training Program Grant, Pre-Doctoral Fellowship","award":["T32 AI007526"],"award-info":[{"award-number":["T32 AI007526"]}]},{"name":"NIAID Emerging and Tropical Infectious Diseases Training Program Grant, Pre-Doctoral Fellowship","award":["R01 AI150917"],"award-info":[{"award-number":["R01 AI150917"]}]},{"name":"NIH\/NIAID","award":["T32 AI007526"],"award-info":[{"award-number":["T32 AI007526"]}]},{"name":"NIH\/NIAID","award":["R01 AI150917"],"award-info":[{"award-number":["R01 AI150917"]}]},{"name":"Sealy Institute of Vaccine Sciences (SIVS) at UTMB","award":["T32 AI007526"],"award-info":[{"award-number":["T32 AI007526"]}]},{"name":"Sealy Institute of Vaccine Sciences (SIVS) at UTMB","award":["R01 AI150917"],"award-info":[{"award-number":["R01 AI150917"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Rift Valley fever (RVF) is a mosquito-borne zoonotic viral disease endemic to Africa and the Middle East. Live-attenuated RVF vaccines have been studied for both veterinary and human use due to their strong immunogenicity and cost-effective manufacturing. The live-attenuated MP-12 vaccine has been conditionally approved for veterinary use in the U.S.A., and next-generation live-attenuated RVF vaccine candidates are being actively researched. Assessing the virulence phenotype of vaccine seeds or lots is crucial for managing vaccine safety. Previously, preweaning 19-day-old outbred CD1 mice have been used to evaluate the MP-12 strain. This study aimed to characterize the relative virulence of three live-attenuated RVF vaccine strains in 19-day-old inbred C57BL\/6 mice: the recombinant MP-12 (rMP-12), the RVax-1, and the \u2206NSs-\u2206NSm-rZH501 strains. Although this mouse model did not show dose-dependent pathogenesis, mice that succumbed to the infection exhibited distinct brain pathology. Mice infected with \u2206NSs-\u2206NSm-rZH501 showed an infiltration of inflammatory cells associated with infected neurons, and focal lesions formed around virus-infected cells. In contrast, mice infected with rMP-12 or RVax-1 showed a minimal association of inflammatory cells in the brain, yet the virus spread diffusely. The preweaning model is likely useful for evaluating host responses to attenuated RVFV strains, although further refinement may be necessary to quantitate the virulence among different RVFV strains or vaccine lots.<\/jats:p>","DOI":"10.3390\/v16070999","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T11:10:28Z","timestamp":1718968228000},"page":"999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Distinct Pathological Changes in Preweaning Mice Infected with Live-Attenuated Rift Valley Fever Virus Strains"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1302-9270","authenticated-orcid":false,"given":"Cigdem","family":"Alkan","sequence":"first","affiliation":[{"name":"Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8832-4645","authenticated-orcid":false,"given":"Eduardo","family":"Jurado-Cobena","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8318-2783","authenticated-orcid":false,"given":"Tetsuro","family":"Ikegami","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"},{"name":"Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev-ento-010715-023819","article-title":"Rift Valley Fever: An Emerging Mosquito-Borne Disease","volume":"61","author":"Linthicum","year":"2016","journal-title":"Annu. Rev. Entomol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Phoenix, I., Lokugamage, N., Nishiyama, S., and Ikegami, T. (2016). Mutational Analysis of the Rift Valley Fever Virus Glycoprotein Precursor Proteins for Gn Protein Expression. Viruses, 8.","DOI":"10.3390\/v8060151"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1038\/emi.2014.71","article-title":"The Rift Valley fever accessory proteins NSm and P78\/NSm-GN are distinct determinants of virus propagation in vertebrate and invertebrate hosts","volume":"3","author":"Kreher","year":"2014","journal-title":"Emerg. Microbes Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3390\/v3050493","article-title":"The Pathogenesis of Rift Valley Fever","volume":"3","author":"Ikegami","year":"2011","journal-title":"Viruses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/s41541-023-00769-w","article-title":"Advancements in Rift Valley fever vaccines: A historical overview and prospects for next generation candidates","volume":"8","author":"Alkan","year":"2023","journal-title":"NPJ Vaccines"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wichgers Schreur, P.J., Bird, B.H., Ikegami, T., Bermudez-Mendez, E., and Kortekaas, J. (2023). Perspectives of Next-Generation Live-Attenuated Rift Valley Fever Vaccines for Animal and Human Use. Vaccines, 11.","DOI":"10.3390\/vaccines11030707"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1099\/0022-1317-66-10-2271","article-title":"Mutagen-directed attenuation of Rift Valley fever virus as a method for vaccine development","volume":"66","author":"Caplen","year":"1985","journal-title":"J. Gen. Virol."},{"key":"ref_8","unstructured":"Hills, R.E. (2013). Issuance of a Conditional License for Rift Valley Fever Vaccine, Modified Live Virus, Center for Veterinary Biologics. Notice no. 13-12."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.vaccine.2015.12.030","article-title":"Safety and immunogenicity of a mutagenized, live attenuated Rift Valley fever vaccine, MP-12, in a Phase 1 dose escalation and route comparison study in humans","volume":"34","author":"Pittman","year":"2016","journal-title":"Vaccine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.vaccine.2015.11.078","article-title":"Rift Valley fever MP-12 vaccine Phase 2 clinical trial: Safety, immunogenicity, and genetic characterization of virus isolates","volume":"34","author":"Pittman","year":"2016","journal-title":"Vaccine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7262","DOI":"10.1128\/JVI.00135-15","article-title":"Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments","volume":"89","author":"Ikegami","year":"2015","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1128\/JVI.02241-15","article-title":"The L-, M- and S-segments of Rift Valley fever virus MP-12 vaccine independently contribute to a temperature-sensitive phenotype","volume":"90","author":"Nishiyama","year":"2016","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41541-022-00536-3","article-title":"Evaluations of rationally designed rift valley fever vaccine candidate RVax-1 in mosquito and rodent models","volume":"7","author":"Ikegami","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6634","DOI":"10.1016\/j.vaccine.2017.10.036","article-title":"Attenuation and protective efficacy of Rift Valley fever phlebovirus rMP12-GM50 strain","volume":"35 Pt B","author":"Ly","year":"2017","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1128\/JVI.02501-07","article-title":"Rift valley fever virus lacking the NSs and NSm genes is highly attenuated, confers protective immunity from virulent virus challenge, and allows for differential identification of infected and vaccinated animals","volume":"82","author":"Bird","year":"2008","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12901","DOI":"10.1128\/JVI.06046-11","article-title":"Rift Valley Fever Virus Vaccine Lacking the NSs and NSm Genes Is Safe, Nonteratogenic, and Confers Protection from Viremia, Pyrexia, and Abortion following Challenge in Adult and Pregnant Sheep","volume":"85","author":"Bird","year":"2011","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9798","DOI":"10.1128\/JVI.78.18.9798-9806.2004","article-title":"NSs protein of Rift Valley fever virus blocks interferon production by inhibiting host gene transcription","volume":"78","author":"Billecocq","year":"2004","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1128\/JVI.75.3.1371-1377.2001","article-title":"Genetic evidence for an interferon-antagonistic function of rift valley fever virus nonstructural protein NSs","volume":"75","author":"Bouloy","year":"2001","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ikegami, T., Narayanan, K., Won, S., Kamitani, W., Peters, C.J., and Makino, S. (2009). Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2alpha phosphorylation. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000287"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6234","DOI":"10.1128\/JVI.02255-10","article-title":"NSs Protein of Rift Valley Fever Virus Promotes Post-Translational Downregulation of the TFIIH Subunit p62","volume":"85","author":"Kalveram","year":"2011","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mudhasani, R., Tran, J.P., Retterer, C., Kota, K.P., Whitehouse, C.A., and Bavari, S. (2016). Protein Kinase R Degradation Is Essential for Rift Valley Fever Virus Infection and Is Regulated by SKP1-CUL1-F-box (SCF)FBXW11-NSs E3 Ligase. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005437"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1128\/JVI.02914-13","article-title":"Virulence factor NSs of rift valley fever virus recruits the F-box protein FBXO3 to degrade subunit p62 of general transcription factor TFIIH","volume":"88","author":"Kainulainen","year":"2014","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Crabtree, M.B., Kent Crockett, R.J., Bird, B.H., Nichol, S.T., Erickson, B.R., Biggerstaff, B.J., Horiuchi, K., and Miller, B.R. (2012). Infection and transmission of Rift Valley fever viruses lacking the NSs and\/or NSm genes in mosquitoes: Potential role for NSm in mosquito infection. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001639"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cartwright, H.N., Barbeau, D.J., and McElroy, A.K. (2020). Rift Valley Fever Virus Is Lethal in Different Inbred Mouse Strains Independent of Sex. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.01962"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/j.1348-0421.2003.tb03424.x","article-title":"Improved recovery of rabies virus from cloned cDNA using a vaccinia virus-free reverse genetics system","volume":"47","author":"Ito","year":"2003","journal-title":"Microbiol. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e02004-20","DOI":"10.1128\/JVI.02004-20","article-title":"Development of a Simian RNA Polymerase I Promoter-Driven Reverse Genetics for the Rescue of Recombinant Rift Valley Fever Virus from Vero Cells","volume":"95","author":"Ikegami","year":"2021","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1128\/JVI.80.6.2933-2940.2006","article-title":"Rescue of infectious rift valley fever virus entirely from cDNA, analysis of virus lacking the NSs gene, and expression of a foreign gene","volume":"80","author":"Ikegami","year":"2006","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1080\/21505594.2016.1195528","article-title":"Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR","volume":"7","author":"Nishiyama","year":"2016","journal-title":"Virulence"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Morrill, J.C., Ikegami, T., Yoshikawa-Iwata, N., Lokugamage, N., Won, S., Terasaki, K., Zamoto-Niikura, A., Peters, C.J., and Makino, S. (2010). Rapid accumulation of virulent rift valley Fever virus in mice from an attenuated virus carrying a single nucleotide substitution in the m RNA. PLoS ONE, 5.","DOI":"10.1371\/annotation\/326c5f5b-3da9-4b0b-b889-28d4f33d2543"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hallam, H.J., Lokugamage, N., and Ikegami, T. (2019). Rescue of infectious Arumowot virus from cloned cDNA: Posttranslational degradation of Arumowot virus NSs protein in human cells. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007904"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lihoradova, O.A., Indran, S.V., Kalveram, B., Lokugamage, N., Head, J.A., Gong, B., Tigabu, B., Juelich, T.L., Freiberg, A.N., and Ikegami, T. (2013). Characterization of Rift Valley Fever Virus MP-12 Strain Encoding NSs of Punta Toro Virus or Sandfly Fever Sicilian Virus. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002181"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8274","DOI":"10.1128\/JVI.00476-06","article-title":"NSm and 78-kilodalton proteins of Rift Valley fever virus are nonessential for viral replication in cell culture","volume":"80","author":"Won","year":"2006","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s12985-016-0573-8","article-title":"Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins","volume":"13","author":"Ly","year":"2016","journal-title":"Virol. J."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wuerth, J.D., and Weber, F. (2016). Phleboviruses and the Type I Interferon Response. Viruses, 8.","DOI":"10.3390\/v8060174"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.virol.2007.01.046","article-title":"Rift Valley fever virus lacking NSm proteins retains high virulence in vivo and may provide a model of human delayed onset neurologic disease","volume":"362","author":"Bird","year":"2007","journal-title":"Virology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S453","DOI":"10.1093\/infdis\/jiy208","article-title":"Ebola Virus Infection in Commonly Used Laboratory Mouse Strains","volume":"218","author":"Haddock","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6161","DOI":"10.1128\/JVI.00337-13","article-title":"Rift Valley Fever Virus Clearance and Protection from Neurologic Disease Are Dependent on CD4+ T Cell and Virus-Specific Antibody Responses","volume":"87","author":"Dodd","year":"2013","journal-title":"J. Virol."},{"key":"ref_39","first-page":"493","article-title":"A simple method of estimating fifty per cent endpoints","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Hyg."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Dodd, K.A., McElroy, A.K., Jones, T.L., Zaki, S.R., Nichol, S.T., and Spiropoulou, C.F. (2014). Rift valley Fever virus encephalitis is associated with an ineffective systemic immune response and activated T cell infiltration into the CNS in an immunocompetent mouse model. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002874"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/7\/999\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:02:14Z","timestamp":1760108534000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/7\/999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,21]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["v16070999"],"URL":"https:\/\/doi.org\/10.3390\/v16070999","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,21]]}}}