Abstract

Macrophages mediate the elimination of pathogens by phagocytosis resulting in the activation of specific signaling pathways that lead to the production of cytokines, chemokines and other factors. Borrelia burgdorferi, the causative agent of Lyme disease, causes a wide variety of pro-inflammatory symptoms. The proinflammatory capacity of macrophages is intimately related to the internalization of the spirochete. However, most receptors mediating this process are largely unknown. We have applied a multiomic approach, including the proteomic analysis of Bburgdorferi-containing phagosome-enriched fractions, to identify surface receptors that are involved in the phagocytic capacity of macrophages as well as their inflammatory output. Sucrose gradient protein fractions of human monocyte-derived macrophages exposed to Bburgdorferi contained the phagocytic receptor, CR3/CD14 highlighting the major role played by these proteins in spirochetal phagocytosis. Other proteins identified in these fractions include C-type lectins, scavenger receptors or Siglecs, of which some are directly involved in the interaction with the spirochete. We also identified the Fc gamma receptor pathway, including the binding receptor, CD64, as involved both in the phagocytosis of, and TNF induction in response to Bburgdorferi in the absence of antibodies. The common gamma chain, FcγR, mediates the phagocytosis of the spirochete, likely through Fc receptors and C-type lectins, in a process that involves Syk activation. Overall, these findings highlight the complex array of receptors involved in the phagocytic response of macrophages to Bburgdorferi.

Author summary

Macrophages eliminate infecting microorganisms through the concerted action of surface receptors and signaling molecules. As a consequence, these cells produce a series of soluble factors that participate in the inflammatory response during infections. The composition of the full complement of receptors that participate in the recognition and internalization of the causative agent of Lyme disease, Borrelia burgdorferi, is largely unknown. We have analyzed the protein composition of phagosomes containing Bburgdorferi from human macrophages and identified a series of surface proteins that may be involved in the process. Through the use of gene silencing techniques, we have determined the participation of several of these receptors both in the internalization of the bacterium and the subsequent inflammatory response. Among these, we have identified the Fc gamma receptor pathway as involved in this process in the absence of antibodies. We have also identified receptors that are directly involved in the attachment of Bburgdorferi, while others seem to have an accessory role in the internalization and/or induction of proinflammatory cytokines in response to the spirochete. These data clarify the complex array of interactions between macrophages and Bburgdorferi and shed light on the overall response to this infectious agent.

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Citation: Carreras-González A, Barriales D, Palacios A, Montesinos-Robledo M, Navasa N, Azkargorta M, et al. (2019) Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions. PLoS Pathog 15(11): e1008163. https://doi.org/10.1371/journal.ppat.1008163