Indispensable roles of TNF signals in protective immunity against Orientia tsutsugamushi infection

Abstract

Abstract Scrub typhus is an emerging tropical disease caused by obligate intracellular bacteria Orientia tsutsugamushi, with over one million cases reported yearly. Patients may develop acute lung injury and multi-organ failure; the worldwide average mortality rate is 6%; however, little is known regarding key immune mediators during infection. Using murine scrub typhus models, we demonstrated the essential role of TNF signals in bacterial control and host protection. Mice lacking both TNF receptors (TNFR1/R2−/−) or receiving anti-TNF-α treatment were highly susceptible to infection with significantly increased tissue bacterial loads, inflammatory responses, and mortality. Their lung- and spleen-derived leukocytes displayed profound defects in total cell numbers and activation status for both innate immunity (NK cells, neutrophils, and macrophages) and adaptive immunity (CD4+ and CD8+ T cells). Infection of TNFR1−/− or TNFR2−/− mice confirmed the requirement of both receptors in efficient control of disease progression, as lacking either one receptor greatly reduced activated CD4+ and CD8+ T effector cells. Together, this study demonstrates a critical and indispensable role of TNF signals in host protective immunity against O. tsutsugamushi infection and severe scrub typhus. Supported by grants from NIH (R01 AI132674, R21 AI156536 and R21 AI153586).