CD14 cooperates with complement receptor 3 to mediate MyD88-independent phagocytosis ofBorrelia burgdorferi

Abstract

Phagocytosis of Borrelia burgdorferi, the causative agent of Lyme disease, is a poorly understood process, despite its importance during the host immune response to infection. B. burgdorferi has been shown to bind to different receptors on the surface of phagocytic cells, including the β 2 integrin, complement receptor 3 (CR3). However, whether these receptors mediate the phagocytosis of the spirochete remains unknown. We now demonstrate that CR3 mediates the phagocytosis of the spirochete by murine macrophages and human monocytes. Interaction of B. burgdorferi with the integrin is not sufficient, however, to internalize the spirochete; phagocytosis requires the interaction of CR3 with the GPI-anchored protein, CD14, independently of TLR/MyD88-induced or inside-out signals. Interestingly, the absence of CR3 leads to marked increases in the production of TNF in vitro and in vivo, despite reduced spirochetal uptake. Furthermore, the absence of CR3 during infection with B. burgdorferi results in the inefficient control of bacterial burdens in the heart and increased Lyme carditis. Overall, our data identify CR3 as a MyD88-independent phagocytic receptor for B. burgdorferi that also participates in the modulation of the proinflammatory output of macrophages. These data also establish a unique mechanism of CR3-mediated phagocytosis that requires the direct cooperation of GPI-anchored proteins.

Macrophage Polarization during Murine Lyme Borreliosis

“…BMDM are commonly used in Lyme disease research as a representative macrophage for investigating in vitro cellular responses to B. burgdorferi infection (26)(27)(28)(29). Following the culture and differentiation of BM precursors into BMDM in our laboratory, these cells appear to take on an uncommitted or M2 phenotype, as determined by flow cytometry expression of NOS2 or CD206 (Fig.…”

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

“…We are currently delineating the underlying mechanism by which OspC affects phagocytosis by macrophage. In this regard, it is known that phagocytosis of B. burgdorferi by macrophages involves several phagocytic receptors (91)(92)(93) and pattern recognition receptors (28,94). One possibility is that OspC alters phagocytic receptor profiles upon contact with macrophages.…”

CD4+T Cells Promote Antibody Production but Not Sustained Affinity Maturation during Borrelia burgdorferi Infection

“…For example, macrophage activation via IFN-␥ or its suppression by IL-10 regulate their ability to phagocytose and destroy spirochetes (45)(46)(47). Importantly, the type of inflammatory cytokines elaborated by macrophages depends on the type of receptors engaged in the initial phagocytosis of B. burgdorferi (48), and this in turn likely is influenced by the activation stage of the macrophage, which itself is dependent on cytokines, such as IFN-␥, elaborated by CD4 T cells and iNKT cells (47). The outcome of these diverse effects of CD4 T cells on the control of Borrelia-induced disease appears strongly tissue dependent.…”