FIG 3.

Model for endothelial infection and renal injury in severe, disseminated O. tsutsugamushi infection. Orientia tsutsugamushi uptake in ECs is followed by cytosolic sensing, where a confirmed role for NOD1 has been described. This leads to the activation of the infected endothelium, with the IL-32-mediated upregulation of inflammatory (IL-1β, IL-6, and IL-8) and adhesion (ICAM-1, VCAM-1, and E selectin) molecules. The increased expression of adhesion molecules in other cell subsets may be involved, as suggested by studies of human patients. The activation of ECs may present a dysfunctional phenotype, with an increased Ang2/Ang1 ratio and altered levels of endothelial nitric oxide synthase (eNOS) and endothelin (ET-1), in which the intranuclear expression and liberation of the alarmin IL-33, along with the upregulated expression of its receptor STL2, play a significant role. Renal tissue damage is enhanced by endothelial apoptosis, where the recruitment of cellular components by chemokine expression and the downregulation of antiapoptotic Bcl-2 may also be involved.