P66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion by Borrelia burgdorferi .

Autor: Tal MC; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Hansen PS; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Ogasawara HA; Department of Pharmaceutical Chemistry, The Cardiovascular Research Institute, Helen Diller Family Comprehensive Cancer Center, Quantitative Biosciences Institute, School of Pharmacy, University of California, San Francisco, CA, USA., Feng Q; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Volk RF; Department of Pharmaceutical Chemistry, The Cardiovascular Research Institute, Helen Diller Family Comprehensive Cancer Center, Quantitative Biosciences Institute, School of Pharmacy, University of California, San Francisco, CA, USA., Lee B; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Casebeer SE; Department of Pharmaceutical Chemistry, The Cardiovascular Research Institute, Helen Diller Family Comprehensive Cancer Center, Quantitative Biosciences Institute, School of Pharmacy, University of California, San Francisco, CA, USA., Blacker GS; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Shoham M, Galloway SD; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Sapiro AL; Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA, USA., Hayes B, Torrez Dulgeroff LB; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Raveh T; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Pothineni VR; Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Dept of Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA., Potula HS; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Dept of Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA., Rajadas J; Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Dept of Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA., Bastounis EE; Interfaculty Institute of Microbiology and Infection Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany., Chou S; Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA, USA., Robinson WH; Division of Immunology and Rheumatology, Departement of Medicine, Stanford Unversity School of Medicine, Stanford, CA, USA., Coburn J; Departments of Medicine and Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA., Weissman IL; Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Zaro BW; Department of Pharmaceutical Chemistry, The Cardiovascular Research Institute, Helen Diller Family Comprehensive Cancer Center, Quantitative Biosciences Institute, School of Pharmacy, University of California, San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 30. Date of Electronic Publication: 2024 Apr 30.
DOI: 10.1101/2024.04.29.591704
Abstrakt: Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "don't eat me" signaling axis between CD47 (ligand) and SIRPα (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRPα. Expression of the gene encoding the protein is required for bacteria to bind SIRPα or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRPα. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.
Databáze: MEDLINE