Characterization of the rhesus macaque (Macaca mulatta) scrub typhus model: Susceptibility to intradermal challenge with the human pathogen Orientia tsutsugamushi Karp.

Autor: Sunyakumthorn P; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand.; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand., Somponpun SJ; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand., Im-Erbsin R; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand., Anantatat T; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand., Jenjaroen K; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand., Dunachie SJ; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand., Lombardini ED; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand., Burke RL; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand., Blacksell SD; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.; Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom., Jones JW; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand., Mason CJ; Department of Veterinary Medicine, United States Army Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand., Richards AL; Viral & Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, MD, United States of America.; Preventive Medicine and Biostatistics Department, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America., Day NPJ; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.; Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom., Paris DH; Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.; Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom.; Department of Medicine, Swiss Tropical and Public Health Institute, Basel, Switzerland.; Faculty of Medicine, University of Basel, Basel, Switzerland.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2018 Mar 09; Vol. 12 (3), pp. e0006305. Date of Electronic Publication: 2018 Mar 09 (Print Publication: 2018).
DOI: 10.1371/journal.pntd.0006305
Abstrakt: Background: Scrub typhus is an important endemic disease in tropical Asia caused by Orientia tsutsugamushi for which no effective broadly protective vaccine is available. The successful evaluation of vaccine candidates requires well-characterized animal models and a better understanding of the immune response against O. tsutsugamushi. While many animal species have been used to study host immunity and vaccine responses in scrub typhus, only limited data exists in non-human primate (NHP) models.
Methodology/principle Findings: In this study we evaluated a NHP scrub typhus disease model based on intradermal inoculation of O. tsutsugamushi Karp strain in rhesus macaques (n = 7). After an intradermal inoculation with 106 murine LD50 of O. tsutsugamushi at the anterior thigh (n = 4) or mock inoculum (n = 3), a series of time course investigations involving hematological, biochemical, molecular and immunological assays were performed, until day 28, when tissues were collected for pathology and immunohistochemistry. In all NHPs with O. tsutsugamushi inoculation, but not with mock inoculation, the development of a classic eschar with central necrosis, regional lymphadenopathy, and elevation of body temperature was observed on days 7-21 post inoculation (pi); bacteremia was detected by qPCR on days 6-18 pi; and alteration of liver enzyme function and increase of white blood cells on day 14 pi. Immune assays demonstrated raised serum levels of soluble cell adhesion molecules, anti-O. tsutsugamushi-specific antibody responses (IgM and IgG) and pathogen-specific cell-mediated immune responses in inoculated macaques. The qPCR assays detected O. tsutsugamushi in eschar, spleen, draining and non-draining lymph nodes, and immuno-double staining demonstrated intracellular O. tsutsugamushi in antigen presenting cells of eschars and lymph nodes.
Conclusions/significance: These data show the potential of using rhesus macaques as a scrub typhus model, for evaluation of correlates of protection in both natural and vaccine induced immunity, and support the evaluation of future vaccine candidates against scrub typhus.
Databáze: MEDLINE
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