Fig 9. A schematic illustration of EC responses in Orientia-infected WT versus IL-33^-/- mice.

In WT mice, O. tsutsugamushi infection increases IL-33 and ST2L expression in ECs, and triggers IL-33 release from the nucleus of stressed or activated ECs. The binding of IL-33 to its membrane-bound receptor ST2L can promote EC activation and apoptosis, as judged by altered expression of Ang proteins. These events collectively contributed to increased ET-1 expression, decreased EC integrity, and increased vascular damage. In the absence of IL-33/ST2L signaling, EC stress and apoptosis are attenuated, partially due to relatively higher Ang1, eNOS, and BCL2 levels, but relatively lower ET-1 levels. The preserved EC integrity, together with the production of other immune cytokines facilitates tissue healing and host survival.