An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection

Lynn Soong, Nicole L. Mendell, Juan Olano, Dedeke Rockx-Brouwer, Guang Xu, Yenny Goez-Rivillas, Claire Drom, Thomas Shelite, Gustavo Valbuena, David Walker, Donald Bouyer

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0004884
JournalPLoS Neglected Tropical Diseases
Volume10
Issue number8
DOIs
StatePublished - Aug 1 2016

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Immunological Models
Scrub Typhus
Infection
Orientia tsutsugamushi
Interleukin-9
Cytokines
Trombiculidae
Neglected Diseases
Bacteria
Chemokine CCL5
Interleukin-13
Mites
Granulocyte Colony-Stimulating Factor
Interleukin-12
Granulocyte-Macrophage Colony-Stimulating Factor
Infection Control
Hypothermia
Gram-Negative Bacteria
Interleukin-1
Inbred C57BL Mouse

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection. / Soong, Lynn; Mendell, Nicole L.; Olano, Juan; Rockx-Brouwer, Dedeke; Xu, Guang; Goez-Rivillas, Yenny; Drom, Claire; Shelite, Thomas; Valbuena, Gustavo; Walker, David; Bouyer, Donald.

In: PLoS Neglected Tropical Diseases, Vol. 10, No. 8, e0004884, 01.08.2016.

Research output: Contribution to journalArticle

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AU - Rockx-Brouwer, Dedeke

AU - Xu, Guang

AU - Goez-Rivillas, Yenny

AU - Drom, Claire

AU - Shelite, Thomas

AU - Valbuena, Gustavo

AU - Walker, David

AU - Bouyer, Donald

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