IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice

PLoS Negl Trop Dis. 2016 Mar 4;10(3):e0004467. doi: 10.1371/journal.pntd.0004467. eCollection 2016 Mar.


Endothelial cells (EC) are the main target for Orientia tsutsugamushi infection and EC dysfunction is a hallmark of severe scrub typhus in patients. However, the molecular basis of EC dysfunction and its impact on infection outcome are poorly understood. We found that C57BL/6 mice that received a lethal dose of O. tsutsugamushi Karp strain had a significant increase in the expression of IL-33 and its receptor ST2L in the kidneys and liver, but a rapid reduction of IL-33 in the lungs. We also found exacerbated EC stress and activation in the kidneys of infected mice, as evidenced by elevated angiopoietin (Ang) 2/Ang1 ratio, increased endothelin 1 (ET-1) and endothelial nitric oxide synthase (eNOS) expression. Such responses were significantly attenuated in the IL-33-/- mice. Importantly, IL-33-/- mice also had markedly attenuated disease due to reduced EC stress and cellular apoptosis. To confirm the biological role of IL-33, we challenged wild-type (WT) mice with a sub-lethal dose of O. tsutsugamushi and gave mice recombinant IL-33 (rIL-33) every 2 days for 10 days. Exogenous IL-33 significantly increased disease severity and lethality, which correlated with increased EC stress and activation, increased CXCL1 and CXCL2 chemokines, but decreased anti-apoptotic gene BCL-2 in the kidneys. To further examine the role of EC stress, we infected human umbilical vein endothelial cells (HUVEC) in vitro. We found an infection dose-dependent increase in the expression of IL-33, ST2L soluble ST2 (sST2), and the Ang2/Ang1 ratio at 24 and 48 hours post-infection. This study indicates a pathogenic role of alarmin IL-33 in a murine model of scrub typhus and highlights infection-triggered EC damage and IL-33-mediated pathological changes during the course of Orientia infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / pathology*
  • Animals
  • Apoptosis*
  • Disease Models, Animal
  • Endothelial Cells / physiology*
  • Female
  • Gene Expression Profiling
  • Host-Pathogen Interactions*
  • Humans
  • Interleukin-33 / metabolism*
  • Kidney / pathology
  • Lung / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orientia tsutsugamushi / pathogenicity*
  • Receptors, Interleukin-1 / metabolism
  • Scrub Typhus / pathology*
  • Severity of Illness Index
  • Survival Analysis


  • Interleukin-33
  • Receptors, Interleukin-1
  • ST2L protein, mouse