<i>Orientia tsutsugamushi</i> binds to multiple C-type lectin receptors

<i>Orientia tsutsugamushi</i>, 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 <i>Orientia</i> 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 <i>Orientia</i> 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 <i>Orientia</i> but contributed to the induction of <i>interleukin-27</i> and <i>cxcl-10</i> mRNA, indicating an immunomodulatory rather than a classical pro-inflammatory role. We also discuss <i>in vivo</i> data that demonstrated upregulation of Mincle and concomitant downregulation of Dectin-1 during <i>Orientia</i> infection. Together, this study identifies multiple CLRs as receptors for <i>Orientia</i>, highlights Mincle as a modulator of innate immunity, and suggests that Mincle-driven immunoregulation helps to shape the inflammatory environment during scrub typhus.