Involvement of toll-like receptor 2 in recognition of Orientia tsutsugamushi by the innate immune system

AuszugScrub typhus is a disease caused by the Gram-negative bacterium Orientia (O.) tsutsugamushi. It is widely distributed in a part of the world known as the „tsutsugamushi triangle“ which covers Asia and the Pacific region including Northern Australia [1]. An estimated one billion people are at risk of acquiring the disease within this endemic area, and the incidence is believed to be around one million new cases every year [2]. Phagocytic cells such as dendritic cells, macrophages, monocytes and neutrophils are the most frequently identified host cells in both humans and mice, especially at the site of pathogen entry [3]. Long before adaptive immunity is induced, an immediate antibacterial defense is provided by the innate immune system. The first critical step is recognition of microbial pathogens by innate immune cells such as macrophages and dendritic cells. These cells express a variety of pattern-recognition receptors (PRRs), which recognize evolutionarily conserved structures in pathogens. Up to now, several classes of PRRs have been recognized such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) [4, 5]. The protective role of TLRs has been recognized to play a role in many infections caused by a diverse set of pathogens, including bacteria, viruses, parasites and fungi [6-9]. TLR2 and TLR4 are the most important receptors for recognition of pathogen surface structures. In vivo, infections with many bacteria, including Rickettsia spp., are controlled by TLR2- or TLR4- dependent pathways [10-12]. While, a deleterious role of TLR2 has been shown in some infection models such as Plasmodium (P.) berghei and Pseudomonas (P.) aeruginosa [13, 14]. The role of innate immune responses mediated by sensing receptors such as TLRs and NLRs in response to O. tsutsugamushi is presently unknown. Moreover, little is known about how innate signaling shapes the early events of infection with O. tsutsugamushi. The goal of this study was to identify the innate receptors involved in recognition of surface structures of O. tsutsugamushi, and to elucidate their role in the experimental scrub typhus mouse model. The following questions guided the experimental investigations: Which receptors are involved in recognition of O. tsutsugamushi surface structures? What is the chemical composition of the O. tsutsugamushi ligand? Which phagocytic cell types are recruited to the regional lymph node early after subcutaneous infection with O. tsutsugamushi, and does recognition by innate receptors influence this recruitment? Which phagocytic cells are infected in the lymph node early after subcutaneous infection with O. tsutsugamushi, and is pathogen dissemination to internal organs dependent on innate receptor signaling? Is the presence of the innate receptor for O. tsutsugamushi required for protection against severe intraperitoneal infection?