The innate immune system is a cooperative network of host defenses that utilizes both soluble components and cellular defenses. Central to innate immune recognition are pattern recognition receptors (PRRs) that recognize pathogen derivatives or altered-self components normally absent from the healthy host. Numerous families of PRRs have been identified including the well-defined Toll-like and Nod-like receptors (TLR and NLRs). In addition to these molecules another large family of PRRs are the scavenger receptor family of proteins. Scavenger receptors (SRs) are structurally unrelated receptors that share the ability to bind polyanionic ligands. This simple definition belies the importance of SRs as PRRs - SRs are archetypal multifunctional receptors, often able to bind ligands of both pathogen and self-origin. SRs are found on cells that patrol potential portals of pathogen entry such as endothelial cells and phagocytes, including macrophages, dendritic cells and microglia. Different cells express distinct repertoires of PRR including SRs providing them with a unique PRR signature, defined by both the cell type and the tissue of origin. In addition to functioning as phagocytic/endocytic receptors, some SRs can both signal independently and cooperatively with other families of PRRs such as the TLRs to respond to pathogens. Thus, through combinatorial signaling, SRs help fine-tune pathogen-specific responses. In addition, SRs are the major class of receptors for modified endogenous ligands providing a link between innate immune activation and sterile inflammatory diseases. However, despite the importance of SRs in pathogen recognition and the emergence of new roles for these molecules in inflammation, the field of scavenger receptor biology has significantly lagged behind that of TLRs and NLRs. Specifically, several essential reagents to study SRs are lacking and hence have limited the study of many of these molecules both in vitro and in vivo. Here we propose to focus on developing scavenger-receptor based reagents. Specifically we propose to develop reagents that 1) will facilitate studies of SR biology and SR-ligand interactions, 2) inhibit the function of SRs in ligand uptake and signaling and 3) that will utilize the SRs expressed by different immune cells to deliver nanoparticle based reagents to specific subpopulations of cells in vivo.

Public Health Relevance

Immune defense against pathogens is initiated after microbial recognition by pattern recognition receptors. Scavenger receptors (SRs) are an important family of such receptors, involved in protection against diverse pathogens. Understanding the role of SRs in immunity is crucial to advance vaccine development and to generate new therapeutics for biodefense and emerging infectious diseases. We propose to generate a comprehensive panel of reagents to facilitate study of these important innate immune receptors

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KE-I (J2))
Program Officer
Prabhudas, Mercy R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
PrabhuDas, Mercy R; Baldwin, Cynthia L; Bollyky, Paul L et al. (2017) A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease. J Immunol 198:3775-3789
Iram, Tal; Ramirez-Ortiz, Zaida; Byrne, Michael H et al. (2016) Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes. J Neurosci 36:5185-92
van der Vos, Kristan E; Abels, Erik R; Zhang, Xuan et al. (2016) Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro Oncol 18:58-69
Gold, Maike; El Khoury, Joseph (2015) ?-amyloid, microglia, and the inflammasome in Alzheimer's disease. Semin Immunopathol 37:607-11
Winkelmann, Evandro R; Widman, Douglas G; Xia, Jingya et al. (2014) Subcapsular sinus macrophages limit dissemination of West Nile virus particles after inoculation but are not essential for the development of West Nile virus-specific T cell responses. Virology 450-451:278-89
Prabhudas, Mercy; Bowdish, Dawn; Drickamer, Kurt et al. (2014) Standardizing scavenger receptor nomenclature. J Immunol 192:1997-2006
Sheedy, Frederick J; Grebe, Alena; Rayner, Katey J et al. (2013) CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 14:812-20
Ramirez-Ortiz, Zaida G; Pendergraft 3rd, William F; Prasad, Amit et al. (2013) The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat Immunol 14:917-26
Frenkel, Dan; Wilkinson, Kim; Zhao, Lingzhi et al. (2013) Scara1 deficiency impairs clearance of soluble amyloid-? by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun 4:2030
Hickman, Suzanne E; El Khoury, Joseph (2013) The neuroimmune system in Alzheimer's disease: the glass is half full. J Alzheimers Dis 33 Suppl 1:S295-302

Showing the most recent 10 out of 12 publications