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

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 β2 integrin,...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (4), p.1228-1232
Main Authors: Hawley, Kelly L, Olson, Chris M., Jr, Iglesias-Pedraz, Juan M, Navasa, Nicolás, Cervantes, Jorge L, Caimano, Melissa J, Izadi, Hooman, Ingalls, Robin R, Pal, Utpal, Salazar, Juan C, Radolf, Justin D, Anguita, Juan
Format: Article
Language:English
Subjects:
Animals
Bacterial infections
Biological Sciences
Borrelia burgdorferi
Borrelia burgdorferi - immunology
Carditis
CD14 antigen
CHO Cells
complement receptor 3
Cooperativity
Cricetinae
Cricetulus
Data processing
Enzyme-Linked Immunosorbent Assay
Heart
Histograms
Humans
Immune response
Infection
Infections
Inflammation
Integrins
Internalization
Lipopolysaccharide Receptors - immunology
Lyme disease
Lyme Disease - immunology
macrophage-1 antigen
Macrophage-1 Antigen - immunology
Macrophages
Macrophages - immunology
Mice
Mice, Inbred C57BL
Monocytes
Monocytes - immunology
myocarditis
Phagocytes
Phagocytosis
Phagocytosis - immunology
Polymerase Chain Reaction
Proteins
Receptors
Spirochaetales
Spirochetes
T cell receptors
Tumor necrosis factor
Tumor Necrosis Factor-alpha - metabolism
tumor necrosis factors
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Summary: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 β2 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1112078109