Phagosomal TLR signaling upon Borrelia burgdorferi infection

Abstract

Internalization and degradation of live Bb within phagosomal compartments of monocytes, macrophages and dendritic cells (DCs), allows for the release of lipoproteins, nucleic acids and other microbial products, triggering a broad and robust inflammatory response. Toll-like receptors (TLRs) are key players in the recognition of spirochetal ligands from whole viable organisms (i.e., vita-PAMPs). Herein we will review the role of endosomal TLRs in the response to the Lyme disease spirochete.

Keywords: Borrelia burgdorferi; Lyme disease; innate immunity; phagosomal signaling; toll-like receptors.

Figure 1

Innate signaling cascade in response to Bb Phagocytosis: Monocytes produce IL-12 to activate Th1 cells and IL6 and IL-1β to activate Th17 cells. Monocytes differentiate into macrophages when stimulated with IFN-γ (produced by Th1 cells) and M-CSF (produced by Th17 cells) and differentiate into dendritic cells when stimulated with IL-4 and IFN-γ. M0 macrophages produce IL-18 to activate Th1 cells and IL-6 and IL-1β to activate Th17 cells, as well as several PMN recruitment chemokines. They also differentiate into M1 macrophages when stimulated with GM-CSF and IFN-γ. Dendritic cells produce IL-6, IL-1β, and TGF-β to activate Th17 cells. Th17 cells produce IL-17, which is a strong PMN attractant. Part of images from Motifolio drawing toolkit (www.motifolio.com) were utilized in the figure preparation.

Figure 2

Phagocytosis of B. burgdorferi: (A) Opsonic-mediated phagocytosis—complement factors, such as C3b and iC3b, bound to the surface of Bb can interact with complement receptors and mediate phagocytosis. Additionally, the immune cells Fc-receptors have the ability to bind to the opsonic antibodies that coat Bb and internalize the pathogen. (B) Conventional phagocytosis—the direct interaction of surface receptors with Bb, such as integrins and C-type lectins, allows for tether of the spirochete to the cell surface. Various PRRs induced signal cascade initiates formation of the phagocytic cup and spirochete engulfment. (C) Coiling phagocytosis—the preferred mechanism of spirochete internalization in which the phagocytic cell uses filopodial protrusions that capture Bb. The filopodial enwrap the spirochete and convert into coiling pseudopods. During this dynamic process FMNL1, mDai1 Arp2/3 complex, and WASP are involved in actin rearrangement of the cell, which then facilitates subsequent phagocytosis of Bb. Following internalization of Bb, the spirochete is degraded within the phagosome thus exposing additional PAMPs to PRR with in the phagosome. The phagosomal signals initiated by Bb generates a robust inflammatory response, including the induction of pro-inflammatory genes and Type I IFNs.

Figure 3

Borrelial RNA is confined to the phagolysosome. Live Bb whose nascent RNA has been stained with Click-iT (5 Uridine) (Green), seen internalized by a human monocyte. Lysosome stained with Lysotracker Red (Red). Colocalization shown as white pixels of the green channel colocacalizing with the red channel.