Abstract
T cells are known to contribute to immune protection against scrub typhus, a potentially fatal infection caused by the obligate intracellular bacterium Orientia (O.) tsutsugamushi. However, the contribution of CD8+ T cells to protection and pathogenesis during O. tsutsugamushi infection is still unknown. Using our recently developed BALB/c mouse model that is based on footpad inoculation of the human-pathogenic Karp strain, we show that activated CD8+ T cells infiltrate spleen and lung during the third week of infection. Depletion of CD8+ T cells with monoclonal antibodies resulted in uncontrolled pathogen growth and mortality. Adoptive transfer of CD8+ T cells from infected animals protected naïve BALB/c mice from lethal outcome of intraperitoneal challenge. In C57Bl/6 mice, the pulmonary lymphocyte compartment showed an increased percentage of CD8+ T cells for at least 135 days post O. tsutsugamushi infection. Depletion of CD8+ T cells at 84 days post infection caused reactivation of bacterial growth. In CD8+ T cell-deficient beta 2-microglobulin knockout mice, bacterial replication was uncontrolled, and all mice succumbed to the infection, despite higher serum IFN-γ levels and stronger macrophage responses in liver and lung. Moreover, we show that CD8+ T cells but not NKT cells were required for hepatocyte injury: elevated concentrations of serum alanine aminotransferase and infection-induced subcapsular necrotic liver lesions surrounded by macrophages were found in C57Bl/6 and CD1d-deficient mice, but not in beta 2-microglobulin knockout mice. In the lungs, peribronchial macrophage infiltrations also depended on CD8+ T cells. In summary, our results demonstrate that CD8+ T cells restrict growth of O. tsutsugamushi during acute and persistent infection, and are required to protect from lethal infections in BALB/c and C57BL/6 mice. However, they also elicit specific pathologic tissue lesions in liver and lung.
Highlights
Orientia (O.) tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium of the Rickettsiaceae family
Orientia (O.) tsutsugamushi is the causative agent of scrub typhus, a potentially fatal disease that is endemic in South East Asia
The obligate intracytoplasmic lifestyle resembles that of many viruses, but among pathogenic bacteria it is unique to O. tsutsugamushi and the closely related Rickettsia spp
Summary
Orientia (O.) tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium of the Rickettsiaceae family. Infection of cardiomyocytes, hepatocytes and epithelial cells has been reported [3,4,5]. Infection of endothelial cells is a hallmark of most Rickettsia species and can be seen in mice infected with O. tsutsugamushi by the intravenous route [6] and in severe human cases of scrub typhus [3, 7]. Protective immunity against O. tsutsugamushi is believed to depend on cellular immunity with interferon (IFN)-γ being the key mediator [8,9,10,11]. Data from in vitro studies suggest that activated macrophages contribute to intracellular killing of O. tsutsugamushi [12, 13]
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