Abstract
Orientia tsutsugamushi, the etiologic agent of scrub typhus, is a mite-borne rickettsia transmitted by the parasitic larval stage of trombiculid mites. Approximately one-third of the world's population is at risk of infection with Orientia tsutsugamushi, emphasizing its importance in global health. In order to study scrub typhus, Orientia tsutsugamushi Karp strain has been used extensively in mouse studies with various inoculation strategies and little success in inducing disease progression similar to that of human scrub typhus. The objective of this project was to develop a disease model with pathology and target cells similar to those of severe human scrub typhus. This study reports an intravenous infection model of scrub typhus in C57BL/6 mice. This mouse strain was susceptible to intravenous challenge, and lethal infection occurred after intravenous inoculation of 1.25×106 focus (FFU) forming units. Signs of illness in lethally infected mice appeared on day 6 with death occurring ∼6 days later. Immunohistochemical staining for Orientia antigens demonstrated extensive endothelial infection, most notably in the lungs and brain. Histopathological analysis revealed cerebral perivascular, lymphohistiocytic infiltrates, focal hemorrhages, meningoencephalitis, and interstitial pneumonia. Disseminated infection of endothelial cells with Orientia in C57BL/6 mice resulted in pathology resembling that of human scrub typhus. The use of this model will allow detailed characterization of the mechanisms of immunity to and pathogenesis of O. tsutsugamushi infection.
Highlights
Orientia tsutsugamushi, a gram-negative obligately intracellular coccobacillus, is the etiologic agent of scrub typhus [1]
Scrub typhus is a disease found in Southeast Asia that infects over 1 million people each year. This disease is caused by the intracellular pathogen Orientia tsutsugamushi transmitted by the bite of chigger mites
The development of animal models that accurately portray human disease is an important step toward understanding and managing disease
Summary
A gram-negative obligately intracellular coccobacillus, is the etiologic agent of scrub typhus [1]. Scrub typhus can cause severe multiorgan failure with a case fatality rate of 7– 15%. Doxycycline, azithromycin, rifampicin, and chloramphenicol are the antibiotics used to treat Orientia infection and are effective if begun early in the disease course [3]. Misdiagnosis, inappropriate antibiotic treatment, and antibiotic failures have occurred, supporting the need for a vaccine [4]. Antigenic heterogeneity and immunity that wanes after infection leading to reinfections are major obstacles to vaccine development [5,6]. The current reemergence of scrub typhus further emphasizes the need for the development of a vaccine, which requires appropriate animal models for determining mechanisms of immunity, candidate vaccine efficacy, and correlates of immune protection
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