Endothelial Activation in Orientia tsutsugamushi Infection Is Mediated by Cytokine Secretion From Infected Monocytes.

Wiwit Tantibhedhyangkul,Ladawan Khowawisetsut,Asma Longkunan,Chawikan Boonwong,Sutthicha Matamnan

doi:10.3389/fcimb.2021.683017

Wiwit Tantibhedhyangkul, Ladawan Khowawisetsut + Show 3 more

Open Access

https://doi.org/10.3389/fcimb.2021.683017

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Abstract

Scrub typhus, caused by Orientia tsutsugamushi, is a common systemic infection in Asia. Delay in diagnosis and treatment can lead to vasculitis in the visceral organs and other complications. The mechanisms that drive endothelial activation and the inflammatory response in O. tsutsugamushi infection remain unknown. In addition, the interaction between monocytes and endothelial cells is still unclear. Here we demonstrate that O. tsutsugamushi-infected human dermal microvascular endothelial cells produced moderate levels of chemokines and low levels of IL-6 and IFN-β, but not TNF or IL-1β. Recombinant TNF and cytokine-rich supernatants from infected monocytes markedly enhanced chemokine production in infected endothelial cells. We also show that TNF and monocyte supernatants, but not O. tsutsugamushi infection of endothelial cells per se, upregulated the endothelial cell surface expression of ICAM-1, E-selectin, and tissue factor. This finding was consistent with the inability of O. tsutsugamushi to induce cytokine secretion from endothelial cells. The upregulation of surface molecules after stimulation with monocyte supernatants was significantly reduced by neutralizing anti-TNF antibodies. These results suggest that endothelial cell activation and response are mainly mediated by inflammatory cytokines secreted from monocytes.

Highlights

Scrub typhus, caused by Orientia tsutsugamushi (OT), is a common cause of acute undifferentiated febrile illness in endemic areas including Asia and Northern Australia (Suttinont et al, 2006; Tantibhedhyangkul et al, 2017b)
Chemokines and IL-6, but Not TNF or IL-1b, Are Weakly Induced by OT Infection in human dermal microvascular endothelial cells (HMECs), and the Response Is Enhanced by Infected Monocyte Supernatants
The complications in rickettsial infections result from vasculitis and vascular injury induced by bacterial invasion into endothelial cells (ECs) and inflammatory response

Summary

Introduction

Scrub typhus, caused by Orientia tsutsugamushi (OT), is a common cause of acute undifferentiated febrile illness in endemic areas including Asia and Northern Australia (Suttinont et al, 2006; Tantibhedhyangkul et al, 2017b). Various complications in different organ systems resulting from vasculitis have been reported in patients (Jeong et al, 2007; Lee et al, 2016). Both Rickettsia and Orientia spp. have tropism for endothelial cells (ECs) (Valbuena and Walker, 2009), whereas OT invades monocytes, dendritic cells and tissue macrophages (Moron et al, 2001; Tantibhedhyangkul et al, 2011; Paris et al, 2012b). We questioned whether EC activation in OT infection is mediated by infected ECs per se or by the cytokines secreted from infected monocytes

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