{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:25:38Z","timestamp":1760059538195,"version":"build-2065373602"},"reference-count":68,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The University of the West Indies, St. Augustine Campus Research and Publication Fund","award":["CRP.5.OCT14.9"],"award-info":[{"award-number":["CRP.5.OCT14.9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>A killed, whole-cell vaccine was produced to induce immunity in dogs against leptospirosis. The vaccine, containing serovar Copenhageni, was produced and administered to 12 beagle dogs at both 8 and 12 weeks of age. Ten unvaccinated dogs of the same age group served as the control group. A live, virulent inoculum of Leptospira (1.52 \u00d7 109\u20134.40 \u00d7 109 leptospires per dog) was used to challenge the dogs at 2 weeks (Study 1) and 14 months (Study 2) post-booster vaccination. At regular intervals, pre- and post-challenge (PC), the microscopic agglutination test (MAT) was performed to measure antibody titers. Leptospiremia and leptospiruria were determined via culture, and the cytokine, biochemical, and pathological profiles of vaccinates and controls were also assessed. A high antibody response was measurable after booster administration. In Study 1 (onset of immunity), acute leptospirosis was observed in five (100%) out of five unvaccinated dogs. In contrast, no acute clinical leptospirosis developed in vaccinated dogs, except in one (20%) dog with mild clinical signs. In Study 2 (duration of immunity), mild clinical signs were observed in two (40%) of the control dogs, while all vaccinated dogs remained clinically normal. The incidence of leptospiruria and leptospiremia PC was lower in the vaccinated dogs compared to the unvaccinated group. Severe thrombocytopenia occurred in 100% (5\/5) of the unvaccinated dogs in Study 1 that exhibited acute severe leptospirosis, whereas 80% (4\/5) of the unvaccinated dogs in Study 2 showed mild to moderate thrombocytopenia 3 days after challenge. Four out of five unvaccinated dogs (80%) in Study 1 exhibited icteric tissues and hemorrhages in the lungs and mucosal surfaces of the stomach and intestines. A high IL-10 to TNF-\u03b1 ratio, observed in the control group of both studies, and severe thrombocytopenia observed in the control group of Study 1, indicative of acute leptospiral disease, were detected. The vaccine prevented acute clinical leptospirosis and reduced the renal carrier state in beagle dogs, and further investigation is required using a larger sample size.<\/jats:p>","DOI":"10.3390\/pathogens14070611","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T05:17:42Z","timestamp":1750396662000},"page":"611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vaccination-Challenge Trials in Beagle Dogs Using Whole-Cell Leptospira interrogans Serovar Copenhageni Vaccine: Prevention of Clinical Leptospirosis, Serological, Leptospiremia, Leptospiruria, Cytokines, Hematological, and Pathological Changes"],"prefix":"10.3390","volume":"14","author":[{"given":"Teola","family":"Noel","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine, Faculty of Medical Sciences, University of the West Indies, St. Augustine 999183, Trinidad and Tobago"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rod","family":"Suepaul","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Faculty of Medical Sciences, University of the West Indies, St. Augustine 999183, Trinidad and Tobago"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-9421","authenticated-orcid":false,"given":"Abiodun A.","family":"Adesiyun","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Faculty of Medical Sciences, University of the West Indies, St. Augustine 999183, Trinidad and Tobago"},{"name":"Department of Production Animal Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, Pretoria 0110, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"ref_1","first-page":"317950","article-title":"Leptospira and Inflammation","volume":"2012","author":"Burth","year":"2012","journal-title":"Mediat. Inflamm."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Allyn, J., Miailhe, A.F., Delmas, B., Marti, L., Allou, N., Jabot, J., and Reignier, J. (2024). Severe leptospirosis in tropical and non-tropical areas: A comparison of two french, multicentre, retrospective cohorts. PLoS Neglected Trop. Dis., 18.","DOI":"10.1371\/journal.pntd.0012084"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Paz, L.N., Dias, C.S., Almeida, D.S., Balassiano, I.T., Medeiros, M.A., Costa, F., Silva, D.N., Reis, J.N., Estrela-Lima, A., and Hamond, C. (2021). Multidisciplinary approach in the diagnosis of acute leptospirosis in dogs naturally infected by Leptospira interrogans serogroup Icterohaemorrhagiae: A prospective study. Comp. Immunol. Microbiol. Infect. Dis., 77.","DOI":"10.1016\/j.cimid.2021.101664"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.vetmic.2009.03.012","article-title":"Leptospira and leptospirosis","volume":"140","author":"Adler","year":"2010","journal-title":"Vet. Microbiol."},{"key":"ref_5","first-page":"1414417","article-title":"Atypical Cases of Leptospirosis: Insights From Georgia","volume":"2024","author":"Dehkordi","year":"2024","journal-title":"Case Rep. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e261369","DOI":"10.1136\/bcr-2024-261369","article-title":"Leptospirosis transmitted from a pet dog","volume":"17","author":"Nakashiro","year":"2024","journal-title":"BMJ Case Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100948","DOI":"10.1016\/j.onehlt.2024.100948","article-title":"Leptospirosis outbreak in Ecuador in 2023: A pilot study for surveillance from a One Health perspective","volume":"19","author":"Orlando","year":"2024","journal-title":"One Health"},{"key":"ref_8","first-page":"609","article-title":"Canine leptospirosis: A One Health approach for improved surveillance, prevention, and interdisciplinary collaboration","volume":"65","author":"Vyn","year":"2024","journal-title":"Can. Vet. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"602","DOI":"10.15585\/mmwr.mm7327a1","article-title":"Human Case of Leptospirosis During a Canine Disease Outbreak\u2014Wyoming, 2023","volume":"73","author":"Waranius","year":"2024","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1863-2378.2009.01240.x","article-title":"Leptospirosis in a Small Animal Veterinarian: Reminder to Follow Standardized Infection Control Procedures","volume":"57","author":"Baer","year":"2010","journal-title":"Zoonoses Public Health"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Smith, A.M., Stull, J.W., and Moore, G.E. (2022). Potential Drivers for the Re-Emergence of Canine Leptospirosis in the United States and Canada. Trop. Med. Infect. Dis., 7.","DOI":"10.3390\/tropicalmed7110377"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1136\/vr.c4965","article-title":"Control of canine leptospirosis in Europe: Time for a change?","volume":"167","author":"Ellis","year":"2010","journal-title":"Vet. Rec."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/avj.13411","article-title":"A comparison of risk factors for canine leptospirosis and seropositivity in New South Wales, Australia","volume":"103","author":"Griebsch","year":"2025","journal-title":"Aust. Vet. J."},{"key":"ref_14","first-page":"245","article-title":"Recent advances in canine leptospirosis: Focus on vaccine development","volume":"6","author":"Klaasen","year":"2015","journal-title":"Vet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Adler, B. (2015). Leptospira and Leptospirosis, Springer. [1st ed.]. Available online: https:\/\/link.springer.com\/10.1007\/978-3-662-45059-8.","DOI":"10.1007\/978-3-662-45059-8"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Furlanello, T., Mazzotta, E., Bertasio, C., D\u2019Incau, M., Bellinati, L., Lucchese, L., and Natale, A. (2024). The Challenge of Bacterial Strain Identification: Leptospira interrogans Serovars Australis in a Dog and Long-Term Clinical Follow-Up. Trop. Med. Infect. Dis., 9.","DOI":"10.3390\/tropicalmed9120285"},{"key":"ref_17","first-page":"256","article-title":"Occurrence of leptospirosis in dogs with renal and\/or hepatic disease in Chennai, India","volume":"63","author":"Sarangi","year":"2024","journal-title":"Indian J. Anim. Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1136\/vr.104694","article-title":"Fifteen-month duration of immunity for the serovar Grippotyphosa fraction of a tetravalent canine leptospirosis vaccine","volume":"182","author":"Grosenbaugh","year":"2018","journal-title":"Vet. Rec."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4103\/1995-7645.391775","article-title":"Vaccine development for leptospirosis: A systematic review","volume":"16","author":"Surendran","year":"2023","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Teixeira, A.F., Cavenague, M.F., Kochi, L.T., Fernandes, L.G., Souza, G.O., de Souza Filho, A.F., Vasconcellos, S.A., Heinemann, M.B., and Nascimento, A.L. (2020). Immunoprotective activity induced by leptospiral outer membrane proteins in hamster model of acute leptospirosis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.568694"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sant\u2019Anna da Costa, R., Di Azevedo, M.I.N., dos Santos Baptista Borges, A.L., Aym\u00e9e, L., Martins, G., and Lilenbaum, W. (2022). Effect of Vaccination against Leptospira on Shelter Asymptomatic Dogs Following a Long-Term Study. Animals, 12.","DOI":"10.3390\/ani12141788"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1016\/j.vaccine.2022.02.021","article-title":"Efficacy of commercially available vaccines against canine leptospirosis: A systematic review and meta-analysis","volume":"40","year":"2022","journal-title":"Vaccine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/S0264-410X(00)00129-8","article-title":"Evidence of cross-protection within Leptospira interrogans in an experimental model","volume":"19","author":"Sonrier","year":"2000","journal-title":"Vaccine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1093\/infdis\/jiq127","article-title":"Cross-protective immunity against leptospirosis elicited by a live, attenuated lipopolysaccharide mutant","volume":"203","author":"Srikram","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Maia, M.A.C., Bettin, E.B., Barbosa, L.N., de Oliveira, N.R., Bunde, T.T., Pedra, A.C.K., Rosa, G.A., da Rosa, E.E.B., Seixas Neto, A.C.P., and Grassmann, A.A. (2022). Challenges for the development of a universal vaccine against leptospirosis revealed by the evaluation of 22 vaccine candidates. Front. Cell Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.940966"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cagliero, J., Villanueva, S.Y.A.M., and Matsui, M. (2018). Leptospirosis Pathophysiology: Into the Storm of Cytokines. Front. Cell Infect. Microbiol., 8.","DOI":"10.3389\/fcimb.2018.00204"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Limothai, U., Lumlertgul, N., Sirivongrangson, P., Kulvichit, W., Tachaboon, S., Dinhuzen, J., Chaisuriyong, W., Peerapornratana, S., Chirathaworn, C., and Praditpornsilpa, K. (2021). The role of leptospiremia and specific immune response in severe leptospirosis. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-94073-z"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41435-020-0095-7","article-title":"Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils","volume":"21","author":"Heeb","year":"2020","journal-title":"Genes Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00584-21","DOI":"10.1128\/IAI.00584-21","article-title":"IL-10 Deficiency Protects Hamsters from Leptospira Infection","volume":"90","author":"Xie","year":"2022","journal-title":"Infect. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bandara, K., Gunasekara, C., Weerasekera, M., Marasinghe, C., Ranasinghe, N., and Fernando, N. (2018). Do the Th17 cells play a role in the pathogenesis of leptospirosis?. Can. J. Infect. Dis. Med. Microbiol., 2018.","DOI":"10.1155\/2018\/9704532"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Maissen-Villiger, C.A., Schweighauser, A., van Dorland, H.A., Morel, C., Bruckmaier, R.M., Zurbriggen, A., and Francey, T. (2016). Expression Profile of Cytokines and Enzymes mRNA in Blood Leukocytes of Dogs with Leptospirosis and Its Associated Pulmonary Hemorrhage Syndrome. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148029"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.vaccine.2022.11.017","article-title":"Cellular and humoral immune responsiveness to inactivated Leptospira interrogans in dogs vaccinated with a tetravalent Leptospira vaccine","volume":"41","author":"Novak","year":"2023","journal-title":"Vaccine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1111\/jvim.16903","article-title":"Updated ACVIM consensus statement on leptospirosis in dogs","volume":"37","author":"Sykes","year":"2023","journal-title":"J. Vet. Intern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1177\/03009858231207020","article-title":"Exudative glomerulonephritis associated with acute leptospirosis in dogs","volume":"61","author":"Hilbe","year":"2023","journal-title":"Vet. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e00869","DOI":"10.1016\/j.heliyon.2018.e00869","article-title":"MAT cross-reactions or vaccine cross-protection: Retrospective study of 863 leptospirosis canine cases","volume":"4","author":"Triger","year":"2018","journal-title":"Heliyon"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chou, L.F., Yang, H.Y., Hung, C.C., Tian, Y.C., Hsu, S.H., and Yang, C.W. (2023). Leptospirosis kidney disease: Evolution from acute to chronic kidney disease. Biomed. J., 46.","DOI":"10.1016\/j.bj.2023.100595"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1128\/CMR.14.2.296-326.2001","article-title":"Leptospirosis","volume":"14","author":"Levett","year":"2001","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1439-0450.2006.00922.x","article-title":"Sero-epidemiology of Canine Leptospirosis in Trinidad: Serovars, Implications for Vaccination and Public Health","volume":"53","author":"Adesiyun","year":"2006","journal-title":"J. Vet. Med. Ser. B"},{"key":"ref_39","first-page":"853","article-title":"Seroepidemiology of leptospirosis in dogs and rats in Trinidad","volume":"31","author":"Suepaul","year":"2014","journal-title":"Trop. Biomed."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5421","DOI":"10.1016\/j.vaccine.2010.06.019","article-title":"Study the efficacy of Leptospira vaccines developed from serovars isolated from Trinidad and comparison with commercial vaccines using a hamster model","volume":"28","author":"Suepaul","year":"2010","journal-title":"Vaccine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"110522","DOI":"10.1016\/j.vetimm.2022.110522","article-title":"Immune response at a vaccine-challenge study using beagle dogs and locally isolated Leptospira spp.","volume":"255","author":"Arjoonsingh","year":"2023","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1017\/S0950268809990902","article-title":"Serovars of Leptospira isolated from dogs and rodents","volume":"138","author":"Suepaul","year":"2010","journal-title":"Epidemiol. Infect."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"779","DOI":"10.4269\/ajtmh.2008.79.779","article-title":"Analyses of vaccination protocols for Leptospira interrogans serovar autumnalis in hamsters","volume":"79","author":"Srikram","year":"2008","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.vetmic.2008.12.021","article-title":"Onset and duration of protective immunity against clinical disease and renal carriage in dogs provided by a bi-valent inactivated leptospirosis vaccine","volume":"137","author":"Minke","year":"2009","journal-title":"Vet. Microbiol."},{"key":"ref_45","unstructured":"Terpstra, W.J. (2003). Human Leptospirosis: Guidance for Diagnosis, Surveillance and Control, World Health Organization. [1st ed.]."},{"key":"ref_46","unstructured":"Plotkin, S.A., Orenstein, W.A., and Offit, P.A. (2008). Vaccines, Elsevier Saunders. [6th ed.]."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Vernel-Pauillac, F., Murray, G.L., Adler, B., Boneca, I.G., and Werts, C. (2021). Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization. PLoS Neglected. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0008970"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0378-1135(03)00152-4","article-title":"Duration of immunity in dogs vaccinated against leptospirosis with a bivalent inactivated vaccine","volume":"95","author":"Klaasen","year":"2003","journal-title":"Vet. Microbiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.vacrep.2016.07.003","article-title":"Efficacy of a multivalent DAPPi-Lmulti canine vaccine against mortality, clinical signs, infection, bacterial excretion, renal carriage and renal lesions caused by Leptospira experimental challenges","volume":"6","author":"Bouvet","year":"2016","journal-title":"Vaccine Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.micinf.2019.03.001","article-title":"Culture-attenuated pathogenic Leptospira lose the ability to survive to complement-mediated-killing due to lower expression of factor H binding proteins","volume":"21","author":"Fraga","year":"2019","journal-title":"Microbes Infect."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5427","DOI":"10.1007\/s00253-018-9047-9","article-title":"Long-term preservation of Leptospira spp.: Challenges and prospects","volume":"102","author":"Philip","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Philip, N., Jani, J., Azhari, N.N., Sekawi, Z., and Neela, V.K. (2021). In vivo and in silico virulence analysis of Leptospira species isolated from environments and rodents in leptospirosis outbreak areas in Malaysia. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.753328"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bouvet, J., Segouffin Cariou, C., Oberli, F., Guiot, A.L., and Cupillard, L. (2024). A New Licensed Quadrivalent Antileptospiral Canine Vaccine Prevents Mortality, Clinical Signs, Infection, Bacterial Excretion, Renal Carriage, and Renal Lesions Caused by Leptospira Australis Experimental Challenge. Vaccines, 12.","DOI":"10.3390\/vaccines12101104"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.vetimm.2013.08.002","article-title":"A new tetravalent canine leptospirosis vaccine provides at least 12 months immunity against infection","volume":"158","author":"Klaasen","year":"2014","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1016\/j.vaccine.2013.05.041","article-title":"A new multivalent (DHPPi\/L4R) canine combination vaccine prevents infection, shedding and clinical signs following experimental challenge with four Leptospira serovars","volume":"31","author":"Wilson","year":"2013","journal-title":"Vaccine"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1136\/vr.101100","article-title":"A novel tetravalent Leptospira bacterin protects against infection and shedding following challenge in dogs","volume":"172","author":"Klaasen","year":"2013","journal-title":"Vet. Rec."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1590\/S1517-83822014000300042","article-title":"Cross-protection between experimental anti-leptospirosis bacterins","volume":"45","author":"Dib","year":"2014","journal-title":"Braz. J. Microbiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1574-6968.1989.tb02385.x","article-title":"Monoclonal antibodies reacting with serogroup and serovar. specific epitopes on different lipopolysaccharide subunits of Leptospira interrogans Serovar Pomona","volume":"1","author":"Adler","year":"1989","journal-title":"FEMS Microbiol. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5626","DOI":"10.1016\/j.vaccine.2021.08.014","article-title":"Protective efficacy of whole-cell inactivated Leptospira vaccines made using virulent or avirulent strains in a hamster model","volume":"39","author":"Jorge","year":"2021","journal-title":"Vaccine"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Vernel-Pauillac, F., and Goarant, C. (2010). Differential cytokine gene expression according to outcome in a hamster model of leptospirosis. PLoS Neglected Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000582"},{"key":"ref_61","first-page":"115","article-title":"Cytokine kinetics in an in vitro whole blood model following an endotoxin challenge","volume":"12","author":"Oliver","year":"1993","journal-title":"Lymphokine Cytokine Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4172","DOI":"10.1128\/IAI.00447-06","article-title":"Proinflammatory and Immunomodulatory Cytokine mRNA Time Course Profiles in Hamsters Infected with a Virulent Variant of Leptospira interrogans","volume":"74","author":"Merien","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Reis, E.A., Hagan, J.E., Ribeiro, G.S., Teixeira-Carvalho, A., Martins-Filho, O.A., Montgomery, R.R., Shaw, A.C., Ko, A.I., and Reis, M.G. (2013). Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. PLoS Neglected Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002457"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1128\/CVI.00397-15","article-title":"Specific CD4+ T-cell reactivity and cytokine release in different clinical presentations of leptospirosis","volume":"22","author":"Volz","year":"2015","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s10096-014-2275-8","article-title":"Severity markers in severe leptospirosis: A cohort study","volume":"34","author":"Mikulski","year":"2015","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.1365-3156.2009.02434.x","article-title":"Coagulation disorders in patients with severe leptospirosis are associated with severe bleeding and mortality","volume":"15","author":"Wagenaar","year":"2010","journal-title":"Trop. Med. Int. Health"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Spiri, A.M., Rodriguez-Campos, S., Matos, J.M., Glaus, T.M., Riond, B., Reusch, C.E., Hofmann-Lehmann, R., and Willi, B. (2017). Clinical, serological and echocardiographic examination of healthy field dogs before and after vaccination with a commercial tetravalent leptospirosis vaccine. BMC Vet. Res., 13.","DOI":"10.1186\/s12917-017-1056-x"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s44149-023-00103-w","article-title":"Clinical features of chronic kidney disease in dogs with the serological presence of Leptospira spp., Ehrlichia canis, and Anaplasma phagocytophilum","volume":"3","year":"2023","journal-title":"Anim. Dis."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/7\/611\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:55:32Z","timestamp":1760032532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/7\/611"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,20]]},"references-count":68,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["pathogens14070611"],"URL":"https:\/\/doi.org\/10.3390\/pathogens14070611","relation":{},"ISSN":["2076-0817"],"issn-type":[{"type":"electronic","value":"2076-0817"}],"subject":[],"published":{"date-parts":[[2025,6,20]]}}}