The innate immune system is a cooperative network of host defenses that utilizes both soluble components and cellular defenses. Central to innate immunerecognition are pattern recognition receptors (PRRs)that recognize pathogen derivatives or altered-self components normallyabsent from the healthy host. Numerousfamilies of PRRs have been identified includingthe well-defined Toll-likeand Nod-like receptors (TLRand 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 SRsas PRRs - SRsare archetypal multifunctional receptors, often able to bind ligands of both pathogen and self-origin. SRsare found on cells that patrol potential portals of pathogen entry such as endothelial cells and phagocytes, including macrophages, dendriticcells andmicroglia. Different cells express distinct repertoires of PRRincludingSRsprovidingthem with a unique PRR signature, defined by both the cell type and the tissue oforigin. In addition to functioning as phagocytic/endocytic receptors, some SRscan both signal independently and cooperatively with other families of PRRs such as the TLRs to respond to pathogens. Thus, through combinatorialsignaling,SRshelp fine-tunepathogen-specific responses. In addition, SRsare the major class of receptors for modified endogenous ligands providinga link between innate immune activation and sterile inflammatorydiseases. However, despite the importance of SRsin pathogen recognition and the emergence of new roles for these molecules in inflammation, the field of scavenger receptor biologyhas significantly lagged behind that of TLRs and NLRs. Specifically, several essential reagents to study SRsare lackingand 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 SRbiology and SR-ligand interactions, 2) inhibitthe function of SRsin ligand uptake and signalingand 3) that will utilizethe SRsexpressed 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

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
5U24AI082660-05
Application #
8445166
Study Section
Special Emphasis Panel (ZAI1-KE-I (J2))
Program Officer
Prabhudas, Mercy R
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$564,699
Indirect Cost
$245,660
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Prabhudas, Mercy; Bowdish, Dawn; Drickamer, Kurt et al. (2014) Standardizing scavenger receptor nomenclature. J Immunol 192:1997-2006
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
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
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
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
Wilkinson, Kim; Boyd, Justin D; Glicksman, Marcie et al. (2011) A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J Biol Chem 286:34914-22