Model for endothelial infection and renal injury in severe, disseminated O. tsutsugamushi infection. 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. Fabián E. Díaz et al. Clin. Microbiol. Rev. 2018; doi:10.1128/CMR.00076-17