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Published on: February 22, 2019
Host transcriptomic profiling of CD-1 outbred mice with severe clinical outcomes following infection with Orientia
Joseph Thiriot1, Yuejin Liang1,2, James Fisher1
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Abstract:
Orientia tsutsugamushi is an obligately intracellular bacterium with endothelial tropism and can cause mild to lethal scrub typhus in humans. No vaccine is available for this reemerging and severely neglected infection. Previous scrub typhus studies have utilized inbred mice, yet such models have intrinsic limitations. Thus, the development of suitable mouse models that better mimic human diseases is in great need for immunologic investigation and future vaccine studies. This study is aimed at establishing scrub typhus in outbred CD-1 mice and defining immune biomarkers related to disease severity. CD-1 mice received O. tsutsugamushi Karp strain via the i.v. route; major organs were harvested at 2-12 days post-infection for kinetic analyses. We found that for our given infection doses, CD-1 mice were significantly more susceptible (90-100% lethal) than were inbred C57BL/6 mice (0-10% lethal). Gross pathology of infected CD-1 mouse organs revealed features that mimicked human scrub typhus, including pulmonary edema, interstitial pneumonia, perivascular lymphocytic infiltrates, and vasculitis. Alteration in angiopoietin/receptor expression in inflamed lungs implied endothelial dysfunction. Lung immune gene profiling using NanoString analysis displayed a Th1/CD8-skewed, but Th2 repressed profile, including novel biomarkers not previously investigated in other scrub typhus models. Bio-plex analysis revealed a robust inflammatory response in CD-1 mice as evidenced by increased serum cytokine and chemokine levels, correlating with immune cell recruitment during the severe stages of the disease. This study provides an important framework indicating a value of CD-1 mice for delineating host susceptibility to O. tsutsugamushi, immune dysregulation, and disease pathogenesis. This preclinical model is particularly useful for future translational and vaccine studies for severe scrub typhus.
Insights
Outbred CD-1 mice are highly susceptible to Orientia tsutsugamushi, developing severe scrub typhus with human-like pathology. This new model reveals immune biomarkers and is valuable for vaccine development against this neglected infection.
Area of Science:
- * Infectious Diseases
- * Immunology
- * Pathogenesis
Background:
- * Scrub typhus, caused by Orientia tsutsugamushi, is a reemerging neglected infectious disease with no available vaccine.
- * Existing inbred mouse models have limitations for studying scrub typhus immunopathology.
- * There is a critical need for better preclinical models to understand disease mechanisms and develop interventions.
Purpose of the Study:
- * To establish and characterize scrub typhus in outbred CD-1 mice.
- * To identify immune biomarkers associated with disease severity in this model.
- * To evaluate the utility of CD-1 mice for future translational and vaccine research.
Main Methods:
- * Outbred CD-1 mice were infected intravenously with Orientia tsutsugamushi (Karp strain).
- * Kinetic analyses of major organs were performed post-infection.
- * Pathology, angiopoietin/receptor expression, lung immune gene profiling (NanoString), and serum cytokine/chemokine levels (Bio-plex) were assessed.
Main Results:
- * CD-1 mice exhibited high susceptibility (90-100% mortality) compared to inbred C57BL/6 mice (0-10% mortality).
- * Observed pathology in CD-1 mice mimicked human scrub typhus, including pulmonary edema, pneumonia, and vasculitis.
- * Immune profiling revealed a Th1/CD8-skewed profile, endothelial dysfunction markers, and elevated inflammatory cytokines/chemokines correlating with disease severity.
Conclusions:
- * Outbred CD-1 mice provide a valuable preclinical model for studying Orientia tsutsugamushi infection and scrub typhus pathogenesis.
- * This model effectively mimics human disease features and host immune responses.
- * The identified immune biomarkers and model's susceptibility are crucial for advancing translational studies and vaccine development for severe scrub typhus.
