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Animal models are essential for elucidating CHIKV pathogenesis and for preclinical evaluation of antiviral strategies; however, a well-characterized model evaluating the effect of different viral doses in AG129 mice remains limited. In this study, we investigated the clinical, virological, and pathological outcomes of CHIKV infection in male AG129 mice inoculated intraperitoneally with different viral doses (10, 100, and 1000 PFU\/mL) of a Brazilian strain belonging to the East\/Central\/South African (ECSA) lineage. Lower-dose inoculation (10 PFU\/mL) resulted in a milder disease course, characterized by transient viremia, limited tissue viral dissemination, minimal histopathological alterations, partial survival, and viral clearance. In contrast, higher doses (\u2265100 PFU\/mL) led to rapid systemic viral dissemination, severe histopathological damage in the spleen, liver, and kidneys, and uniform lethality. Viral RNA was detected in serum and multiple organs in a time-dependent manner, with limited differences among inoculum doses in most tissues. Notably, dose-related differences were observed in specific compartments and time points, particularly in hind-limb muscles at early time points and in serum at later stages.<\/jats:p>","DOI":"10.3390\/pathogens15050454","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T09:01:24Z","timestamp":1776848484000},"page":"454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical, Virological, and Pathological Outcomes Associated with Viral Dose in AG129 Mice Infected with Chikungunya Virus: An In Vivo Model to Study Viral Pathogenesis and Antiviral Preclinical Evaluation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3545-8551","authenticated-orcid":false,"given":"Mar\u00edlia Mazzi","family":"Moraes","sequence":"first","affiliation":[{"name":"Institute of Chemistry, S\u00e3o Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9465-8471","authenticated-orcid":false,"given":"Nat\u00e1lia","family":"de Godoy","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Maffud","family":"Cilli","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, S\u00e3o Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2898-8191","authenticated-orcid":false,"given":"Paulo Ricardo da Silva","family":"Sanches","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1128\/mr.58.3.491-562.1994","article-title":"The alphaviruses: Gene expression, replication, and evolution","volume":"58","author":"Strauss","year":"1994","journal-title":"Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1473-3099(07)70107-X","article-title":"Chikungunya, an epidemic arbovirosis","volume":"7","author":"Pialoux","year":"2007","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Weaver, S.C. (2014). Arrival of chikungunya virus in the new world: Prospects for spread and impact on public health. PLoS Neglected Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002921"},{"key":"ref_4","first-page":"192","article-title":"A laboratory technique for studying the insect transmission of animal viruses, employing a bat-wing membrane, demonstrated with two African viruses","volume":"54","author":"Ross","year":"1956","journal-title":"Epidemiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rama, K., de Roo, A.M., Louwsma, T., Hofstra, H.S., Gurgel do Amaral, G.S., Vondeling, G.T., Postma, M.J., and Freriks, R.D. (2024). Clinical outcomes of chikungunya: A systematic literature review and meta-analysis. PLoS Neglected Trop. Dis., 18.","DOI":"10.1371\/journal.pntd.0012254"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1016\/S0140-6736(23)00641-4","article-title":"Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: A double-blind, multicentre, randomised, placebo-controlled, phase 3 trial","volume":"401","author":"Schneider","year":"2023","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/S0140-6736(25)00345-9","article-title":"Chikungunya virus virus-like particle vaccine safety and immunogenicity in adolescents and adults in the USA: A phase 3, randomised, double-blind, placebo-controlled trial","volume":"405","author":"Richardson","year":"2025","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S482","DOI":"10.1093\/infdis\/jiw284","article-title":"Animal models of chikungunya virus infection and disease","volume":"214","author":"Haese","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Milligan, G.N., Sarathy, V.V., Infante, E., Li, L., Campbell, G.A., Beatty, P.R., Harris, E., Barrett, A.D., and Bourne, N. (2015). A dengue virus type 4 model of disseminated lethal infection in AG129 mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125476"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1128\/JVI.01320-14","article-title":"A lethal murine infection model for dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease","volume":"89","author":"Sarathy","year":"2015","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Aliota, M.T., Caine, E.A., Walker, E.C., Larkin, K.E., Camacho, E., and Osorio, J.E. (2016). Characterization of lethal Zika virus infection in AG129 mice. PLoS Neglected Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004750"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nunes, M.R., Faria, N.R., de Vasconcelos, J.M., Golding, N., Kraemer, M.U., de Oliveira, L.F., Azevedo, R.D., da Silva, D.E., da Silva, E.V., and da Silva, S.P. (2015). Emergence and potential for spread of Chikungunya virus in Brazil. BMC Med., 13.","DOI":"10.1186\/s12916-015-0348-x"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"764","DOI":"10.3201\/eid1305.070015","article-title":"Chikungunya virus in US travelers returning from India, 2006","volume":"13","author":"Lanciotti","year":"2007","journal-title":"Emerg. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.bsheal.2025.09.008","article-title":"Advances and perspectives for animal models of chikungunya virus infection","volume":"7","author":"Zou","year":"2025","journal-title":"Biosaf. Health"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.3390\/v16101534","article-title":"Comparison of Chikungunya Virus-Induced Disease Progression and Pathogenesis in Type-I Interferon Receptor-Deficient Mice (A129) and Two Wild-Type (129Sv\/Ev and C57BL\/6) Mouse Strains","volume":"16","author":"Graham","year":"2024","journal-title":"Viruses"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Venugopalan, A., Ghorpade, R.P., and Chopra, A. (2014). Cytokines in acute chikungunya. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111305"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Haist, K.C., Burrack, K.S., Davenport, B.J., and Morrison, T.E. (2017). Inflammatory monocytes mediate control of acute alphavirus infection in mice. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006748"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41579-025-01177-8","article-title":"Chikungunya virus and other emerging arthritogenic alphaviruses","volume":"23","author":"Lecuit","year":"2025","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2436","DOI":"10.1093\/cid\/ciaa1038","article-title":"Fatal outcome of chikungunya virus infection in Brazil","volume":"73","author":"Cavalcante","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e20190580","DOI":"10.1590\/0037-8682-0580-2019","article-title":"Estimated mortality rate and leading causes of death among individuals with chikungunya in 2016 and 2017 in Brazil","volume":"53","author":"Frutuoso","year":"2020","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41572-023-00429-2","article-title":"Chikungunya fever","volume":"9","author":"Bartholomeeusen","year":"2023","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/S1473-3099(23)00739-9","article-title":"Risk of death following chikungunya virus disease in the 100 Million Brazilian Cohort, 2015\u20132018: A matched cohort study and self-controlled case series","volume":"24","author":"Pescarini","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_23","first-page":"1718","article-title":"Epidemiology of Chikungunya Hospitalizations, Brazil, 2014\u20132024","volume":"31","author":"Porto","year":"2025","journal-title":"Emerg. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"882","DOI":"10.4269\/ajtmh.13-0403","article-title":"Incubation periods of mosquito-borne viral infections: A systematic review","volume":"90","author":"Rudolph","year":"2014","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_25","first-page":"973516","article-title":"Molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis","volume":"2013","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_26","first-page":"001644","article-title":"Alphaviruses: Host pathogenesis, immune response, and vaccine & treatment updates","volume":"102","author":"Weber","year":"2021","journal-title":"J. Gen. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Rathore, A.P., Mantri, C.K., Tan, M.W., Shirazi, R., Nishida, A., Aman, S.A., Morrison, J., and St. John, A.L. (2021). Immunological and pathological landscape of dengue serotypes 1-4 infections in immune-competent mice. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.681950"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ribeiro, Y.P., Falc\u00e3o, L.F., Smith, V.C., de Sousa, J.R., Pagliari, C., Franco, E.C., Cruz, A.C., Chiang, J.O., Martins, L.C., and Nunes, J.A. (2023). Comparative analysis of human hepatic lesions in dengue, yellow fever, and chikungunya: Revisiting histopathological changes in the light of modern knowledge of cell pathology. Pathogens, 12.","DOI":"10.3390\/pathogens12050680"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e70047","DOI":"10.1002\/rmv.70047","article-title":"A Review of Arboviral-Induced Liver Damage: Acute Manifestations and Speculative Links to Chronic Inflammation","volume":"35","author":"Wang","year":"2025","journal-title":"Rev. Med. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.chom.2024.02.011","article-title":"Pathophysiology of chikungunya virus infection associated with fatal outcomes","volume":"32","author":"Fumagalli","year":"2024","journal-title":"Cell Host Microbe"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"727","DOI":"10.4269\/ajtmh.2007.77.727","article-title":"A major epidemic of chikungunya virus infection on Reunion Island, France, 2005\u20132006","volume":"77","author":"Renault","year":"2007","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1017\/S0950268808001167","article-title":"Atypical Chikungunya virus infections: Clinical manifestations, mortality and risk factors for severe disease during the 2005\u20132006 outbreak on Reunion","volume":"137","author":"Economopoulou","year":"2009","journal-title":"Epidemiol. Infect"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ozden, S., Huerre, M., Riviere, J.-P., Coffey, L.L., Afonso, P.V., Mouly, V., de Monredon, J., Roger, J.-C., El Amrani, M., and Yvin, J.-L. (2007). Human Muscle Satellite Cells as Targets of Chikungunya Virus Infection. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000527"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8021","DOI":"10.1128\/JVI.02603-09","article-title":"Chikungunya virus arthritis in adult wild-type mice","volume":"84","author":"Gardner","year":"2010","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"259","DOI":"10.4049\/jimmunol.1202177","article-title":"A pathogenic role for CD4+ T cells during Chikungunya virus infection in mice","volume":"190","author":"Claser","year":"2013","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Filippone, C., Legros, V., Jeannin, P., Choumet, V., Butler-Browne, G., Zoladek, J., Mouly, V., Gessain, A., and Ceccaldi, P.E. (2020). Arboviruses and muscle disorders: From disease to cell biology. Viruses, 12.","DOI":"10.3390\/v12060616"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Pawelek, K.A., Huynh, G.T., Quinlivan, M., Cullinane, A., Rong, L., and Perelson, A.S. (2012). Modeling within-host dynamics of influenza virus infection including immune responses. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002588"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/5\/454\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T09:37:23Z","timestamp":1776850643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/5\/454"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["pathogens15050454"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15050454","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]}}}