Orientia tsutsugamushi binds to multiple C-type lectin receptors

TL;DR

This study identifies several C-type lectin receptors that recognize Orientia tsutsugamushi, a bacterium causing scrub typhus, and highlights Mincle's role in modulating immune responses.

Contribution

The study reveals multiple C-type lectin receptors involved in Orientia recognition and defines Mincle's immunomodulatory role during infection.

Findings

Orientia tsutsugamushi binds to mouse CLRs Mincle, Dectin-1, Langerin, and DCL-1, as well as human DC-SIGN.

Mincle binding is Ca²+-dependent and involves carbohydrate-specific recognition.

Mincle modulates cytokine responses during Orientia infection, influencing interleukin-27 and cxcl-10 mRNA expression.

Abstract

Orientia tsutsugamushi, the agent of scrub typhus, is an obligate intracellular bacterium whose atypical cell wall lacks many classical pathogen-associated molecular patterns but is enriched in neutral glycans. Its recognition by phagocytes is driven by a heat-stable ligand that triggers innate cytokine responses, yet the nature of this ligand and the receptors sensing it remain incompletely understood. While activation of innate immunity via toll-like (TLR) and nucleotide-binding and oligomerization domain-like receptors has been described, recognition via C-type lectin receptors (CLRs) has remained largely unexplored. Using a flow cytometry-based screening assay with a library of CLR-Fc fusion proteins, we demonstrate binding of Orientia to four mouse CLRs, including Mincle, Dectin-1, Langerin, and DCL-1, as well as to human DC-SIGN. Binding to Mincle was Ca²+-dependent, indicating carbohydrate-specific recognition. In bone marrow-derived dendritic cells (BMDC), heat-inactivated Orientia induced transcriptional upregulation of Mincle in a MyD88-dependent manner, suggesting cross talk between TLR and CLR pathways. Mincle was dispensable for TNF-α induction in BMDC stimulated with Orientia but contributed to the induction of interleukin-27 and cxcl-10 mRNA, indicating an immunomodulatory rather than a classical pro-inflammatory role. We also discuss in vivo data that demonstrated upregulation of Mincle and concomitant downregulation of Dectin-1 during Orientia infection. Together, this study identifies multiple CLRs as receptors for Orientia, highlights Mincle as a modulator of innate immunity, and suggests that Mincle-driven immunoregulation helps to shape the inflammatory environment during scrub typhus.

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