Protective and Pathogenic Roles of CD8+ T Lymphocytes in Murine Orientia tsutsugamushi Infection.
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.
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Matthias
M
Hauptmann
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Julia
J
Kolbaum
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Stefanie
S
Lilla
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
David
D
Wozniak
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Mohammad
M
Gharaibeh
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.|Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Bernhard
B
Fleischer
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Christian A
CA
Keller
D019264:Adoptive Transfer; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000097:blood; D008168:Lung / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012285:Orientia tsutsugamushi; D012612:Scrub Typhus / Q000276:immunology* / Q000628:therapy; D013154:Spleen / Q000473:pathology
D000907:Antibodies, Bacterial; C000611649:IFNG protein, mouse; D007371:Interferon-gamma