Immune-Medicated Angiopoietin/Tie2 Expression and Renal Injury in Murine Orientia tsutsugamushi Infection Models

Abstract Scrub typhus caused by O. tsutsugamushi infection is a life-threatening disease endemic in the Asia-Pacific region; however, its molecular pathogenesis remains unclear. Using new mouse models, we have reported that endothelial cell (EC)-targeted O. tsutsugamushi infection, acute tissue injury, and kidney bacterial persistency are pathological hallmarks, which mimic human scrub typhus. In this study, we focused on the regulation of vascular growth factor angiopoietin-1 (Ang1), its antagonist Ang2, and their specific Tie2 receptor in the kidneys of C57BL/6 mice. At D6 (disease onset) and D10 (prior to host death), infected kidneys had high Ang2/Ang1 ratio, but low Tie2 levels, and a progressive loss of glomerulus integrity. These renal injury signs were associated with increased influx of MPO+ neutrophils and CD3+T cells and expression of Th1 cytokines (TNF-α, IFN-γ, CXCL9) in the kidneys. Notable, we found a significant, time-dependent increase in alarmin expression (IL-33 and IL-36γ) preferentially in the kidneys, rather than in other organs, even though kidneys contained much lower bacterial loads than other organs. To test if host alarmin molecules contribute to disease severity, we compared pathology in lethally-infected WT and IL-33−/− mice, as well as rIL-33-injected WT mice. IL-33 deficiency promoted BCL2, Ang1, and eNOS expression and reduced cellular apoptosis in inflamed kidneys. In contrast, rIL-33 injunctions markedly exacerbated vascular stress and renal injury and increased host susceptibility to sublethal infection. Together, this study reveals that an immune-regulated expression of the Ang1/Tie2 axis can influence renal injury during infection. It helps understand the pathogenesis of severe scrub typhus.