title: An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection.
abstract: Scrub typhus is a neglected tropical disease, caused by Orientia tsutsugamushi, a Gram-negative bacterium that is transmitted to mammalian hosts during feeding by Leptotrombidium mites and replicates predominantly within endothelial cells. Most studies of scrub typhus in animal models have utilized either intraperitoneal or intravenous inoculation; however, there is limited information on infection by the natural route in murine model skin or its related early host responses. Here, we developed an intradermal (i.d.) inoculation model of scrub typhus and focused on the kinetics of the host responses in the blood and major infected organs. Following ear inoculation with 6 x 104 O. tsutsugamushi, mice developed fever at 11-12 days post-infection (dpi), followed by marked hypothermia and body weight loss at 14-19 dpi. Bacteria in blood and tissues and histopathological changes were detected around 9 dpi and peaked around 14 dpi. Serum cytokine analyses revealed a mixed Th1/Th2 response, with marked elevations of MCP-1/CCL2, MIP-1α/CCL3 and IL-10 at 9 dpi, followed by increased concentrations of pro-inflammatory markers (IL-6, IL-12, IFN-γ, G-CSF, RANTES/CCL5, KC/CCL11, IL-1α/β, IL-2, TNF-α, GM-CSF), as well as modulatory cytokines (IL-9, IL-13). Cytokine levels in lungs had similar elevation patterns, except for a marked reduction of IL-9. The Orientia 47-kDa gene and infectious bacteria were detected in several organs for up to 84 dpi, indicating persistent infection. This is the first comprehensive report of acute scrub typhus and persistent infection in i.d.-inoculated C57BL/6 mice. This is a significant improvement over current murine models for Orientia infection and will permit detailed studies of host immune responses and infection control interventions.
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Mendell
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Olano
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Dedeke
authors.initials: D
authors.lastname: Rockx-Brouwer
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Guang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Yenny
authors.initials: Y
authors.lastname: Goez-Rivillas
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Drom
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Shelite
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Valbuena
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Walker
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, School of Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Bouyer
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007271:Injections, Intradermal; D008099:Liver / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012285:Orientia tsutsugamushi; D012612:Scrub Typhus / Q000276:immunology*; D014611:Vaccination / Q000379:methods
chemical_list: D016207:Cytokines