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.
Highlights
Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus with a geographical distribution that encompasses much of the Asia-Pacific region [1]
We compared the severity of disease between wild-type (WT) and IL-33-/- mice infected with O. tsutsugamushi and used exogenous IL-33 to further examine the function of IL-33 during the infection
Since Orientia lacks the classical ligands for TLR2/ 4 stimulation, we speculated that the host Damage-associated molecular pattern molecules (DAMPs) molecule, IL-33 plays a role in modulating inflammation responses in this infection
Summary
Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus with a geographical distribution that encompasses much of the Asia-Pacific region [1]. Scrub typhus is a neglected but important tropical disease, which puts one-third of the world’s population at risk. Scrub typhus can cause severe multi-organ failure with a relatively high mortality rate [8]. Several antibiotics (doxycycline, azithromycin, rifampicin, chloramphenicol, etc.) have been used to treat Orientia infection. These antibiotics are effective if given early [9,10,11,12], misdiagnosis, inappropriate antibiotic treatment, and antibiotic failures have occurred, emphasizing the need for a vaccine and alternative therapeutics [1]. Understanding the molecular mechanism of the infection will be beneficial for vaccine design and future therapeutic strategies
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