title: IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Shelite
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Mendell
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Trent
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Jiaren
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Gong
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Guang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Haitao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Bouyer
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Sealy Center for Vaccine Development, Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D000067596:Interleukin-33 / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D008168:Lung / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012285:Orientia tsutsugamushi / Q000472:pathogenicity*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012612:Scrub Typhus / Q000473:pathology*; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D000067596:Interleukin-33; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse