Laboratory of  Molecular Immunology 

Philip M. Murphy, M.D.

Chief, Laboratory of Molecular Immunology
Chief, Molecular Signaling Section

Molecular Signaling Section

Description of Research Program

This laboratory studies G protein-coupled receptors of the immune system. These include a large family of chemokine receptors and a smaller group of classical chemoattractant receptors, which, together, differentially regulate specific leukocyte trafficking in support of innate and adaptive immune responses.

The goal of the lab is to delineate the precise mechanisms by which the receptors relay chemotactic signals to cells and to identify their exact physiologic roles both in immunoregulation and in immunologically mediated disease. The approaches used are to isolate specific chemoattractant receptors by molecular cloning, to examine their signal transduction properties both in model cell systems and in primary cells, and to study their biology in gene knockout mice.

Further, the lab has a program in human immunogenomics in which genetic polymorphisms discovered in candidate chemoattractant or chemoattractant receptor genes are checked for effects on biochemical function and for associations with specific diseases. Our discoveries include

1. Identification of the first CXC, CC and CX3C chemokine receptor subtypes, as well as numerous other members of the chemokine receptor family, and characterization of their ligand and leukocyte specificities
2. Identification and characterization of the f-Met-Leu-Phe receptor (FPR) family
3. Creation of receptor knockout mice for analysis of biological function
4. Identification of CCR5, and demonstration that CCR5 is a major HIV receptor in vivo by analysis of the defective genetic variant CCR5Δ32
5. Characterization of the first viral mimics of chemokine receptors
6. Demonstration that amyloid β, the major pathologic protein in Alzheimer's disease, is a functional ligand for the fMLF receptor subtype FPRL1
7. Discovery of novel genetic risk factors in man in atherosclerosis, HIV/AIDS, West Nile virus infection, and kidney transplant rejection

There are projects ongoing in the lab extending each of these observations.

Awards

NIH Merit Award (1992); NIH Director's Award (1994, 1996); NIH Senior Biomedical Research Service (1998); American Society for Clinical Investigation (1992); Association of American Physicians (1997).

Memberships

• American Association for the Advancement of Science
• American Society for Cell Biology
• American Society for Clinical Investigation
• American Society of Biochemistry and Molecular Biology
• Association of American Physicians
• American Association of Immunologists
• Society for Leukocyte Biology

Editorial Boards

• Cellular Immunology
• Journal of Leukocyte Biology
• Journal of Biological Chemistry
• Journal of Immunology
• Viral Immunology
• inScight

Research Group Members

Ji-Liang Gao, David McDermott, Lee Tiffany, Joan Sechler, Jana Barlic, Kengo Furuichi, Jean Lim.

Selected Publications

(View list in PubMed.)

Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol. 2004. 173: 4030-4039.

Barlic J, McDermott DH, Merrell MN, Gonzales J, Via LE, Murphy PM. Interleukin (IL)-15 and IL-2 reciprocally regulate expression of the chemokine receptor CX3CR1 through selective NFAT1- and NFAT2-dependent mechanisms. J Biol Chem. 2004. 279: 48520-48534.

McDermott DH, Fong AM, Yang Q, Sechler JM, Cupples LA, Merrell MN, Wilson PW, D'Agostino RB, O'Donnell CJ, Patel DD, Murphy PM. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest. 2003. 111: 1241-1250.

Combadiere C, Potteaux S, Gao JL, Esposito B, Casanova S, Lee EJ, Debre P, Tedgui A, Murphy PM, Mallat Z. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation. 2003. 107: 1009-1016.

Schwarz M, Murphy PM. Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-kappa B and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol. 2001. 167: 505-513.

McDermott DH, Colla JS, Kleeberger CA, Plankey M, Rosenberg PS, Smith ED, Zimmerman PA, Combadiere C, Leitman SF, Kaslow RA, Goedert JJ, Berger EA, O'Brien TR, Murphy PM. Genetic polymorphism in CX3CR1 and risk of HIV disease. Science. 2000. 290: 2031.

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