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

Sunyakumthorn, Piyanate and Somponpun, Suwit J. and Im-Erbsin, Rawiwan and Anantatat, Tippawan and Jenjaroen, Kemajittra and Dunachie, Susanna J. and Lombardini, Eric D. and Burke, Robin L. and Blacksell, Stuart D. and Jones, James W. and Mason, Carl J. and Richards, Allen L. and Day, Nicholas P. J. and Paris, Daniel H.. (2018) Characterization of the rhesus macaque (Macaca mulatta) scrub typhus model : Susceptibility to intradermal challenge with the human pathogen Orientia tsutsugamushi Karp. PLoS Neglected Tropical Diseases, 12 (3). e0006305.

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Abstract

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.; 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.; 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Paris, Daniel Henry
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Public Library of Science
ISSN:1935-2727
e-ISSN:1935-2735
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:29 Apr 2019 12:54
Deposited On:02 Jul 2018 09:29

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