Abstract
BackgroundScrub typhus, a febrile illness of substantial incidence and mortality, is caused by infection with the obligately intracellular bacterium Orientia tsutsugamushi. It is estimated that there are more than one million cases annually transmitted by the parasitic larval stage of trombiculid mites in the Asia-Pacific region. The antigenic and genetic diversity of the multiple strains of O. tsutsugamushi hinders the advancement of laboratory diagnosis, development of long-lasting vaccine-induced protection, and interpretation of clinical infection. Despite the life-threatening severity of the illness in hundreds of thousands of cases annually, 85–93% of patients survive, often without anti-rickettsial treatment. To more completely understand the disease caused by Orientia infection, animal models which closely correlate with the clinical manifestations, target cells, organ involvement, and histopathologic lesions of human cases of scrub typhus should be employed. Previously, our laboratory has extensively characterized two relevant C57BL/6 mouse models using O. tsutsugamushi Karp strain: a route-specific intradermal model of infection and persistence and a hematogenously disseminated dose-dependent lethal model.Principal findingsTo complement the lethal model, here we illustrate a sublethal model in the same mouse strain using the O. tsutsugamushi Gilliam strain, which resulted in dose-dependent severity of illness, weight loss, and systemic dissemination to endothelial cells of the microcirculation and mononuclear phagocytic cells. Histopathologic lesions included expansion of the pulmonary interstitium by inflammatory cell infiltrates and multifocal hepatic lesions with mononuclear cellular infiltrates, renal interstitial lymphohistiocytic inflammation, mild meningoencephalitis, and characteristic typhus nodules.SignificanceThese models parallel characteristics of human cases of scrub typhus, and will be used in concert to understand differences in severity which lead to lethality or host control of the infection and to address the explanation for short duration of heterologous immunity in Orientia infection.
Highlights
Scrub typhus is a potentially fatal febrile illness caused by infection with the obligately intracellular bacterium Orientia tsutsugamushi
The lack of appropriate animal models of scrub typhus has left a void in the fundamental knowledge necessary to develop a vaccine, such as mechanisms which contribute to disease severity and immunity
We report a sublethal inbred murine model for scrub typhus using the intradermal and intravenous routes of inoculation, which are comparable to the natural route of chigger-bite transmission and subsequent hematogenous spread
Summary
Scrub typhus is a potentially fatal febrile illness caused by infection with the obligately intracellular bacterium Orientia tsutsugamushi. The geographic range of confirmed cases includes Asia, islands of the Pacific and Indian Ocean, and northern Australia; areas home to more than onethird of the world’s population [1]. Growing evidence implicates a range of Orientia infection outside of the known endemic region, including a case transmitted in the United Arab Emirates, serological and molecular data from Africa and South America and molecular evidence which has suggested Orientia species are present in Europe [2,3,4,5,6,7,8,9,10]. Editor: Andrew S Azman, Johns Hopkins Bloomberg School of Public Health, UNITED STATES
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