Claudio G. Giraudo, PhD
Assistant Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine
Contact InformationThe Children's Hospital of Philadelphia
Abramson Research Center, Room 816C
Philadelphia, PA 19104
Office: 267-425 –2124
Immunobiology and Experimental Pathology
The research of the lab aims to understand how immune cells kill virus-infected cells and tumors
Cell Biology, Cytotoxic T-cells, Natural Killer cells, cell-mediated cytotoxicity, Primary Immune Deficiencies, HLH, Membrane Trafficking, Exocytosis, Membrane fusion, SNAREs.
Cytotoxic T-cells (CTLs) and Natural Killer (NK) cells are key components of the innate and adaptive immune system responsible to destroy virus-infected and cancer cells. CTL and NK cells perform this fundamental function by releasing apoptotic proteins contained within lytic granules at the contact area with a target cell known as Immunological Synapse. Patients with defects in these processes most commonly manifest with Familial Hemophagocytic Lymphohistiocytosis (FHL), a fulminant Primary Immunodeficiency characterized by a disproportionate deregulation of the immune system. In particular, my lab is interested in determine how gene mutations affect the molecular machinery that control the membrane fusion steps required for the cytotoxic immune response. By providing a better understanding of WT and mutant FHL-associated proteins, our studies will shed new light on the critical mechanisms that control cell-killing pathways in CTL and NK cells. To study how these processes are achieved we utilize multidisciplinary approaches including biochemical reconstitution, proteomics, biophysical analysis, live cell imaging and Total Internal Reflection Microscopy. In addition, we are developing novel simplified fusion assays that will help us to elucidate the molecular mechanism of how lytic granule exocytosis is controlled in time and space. In summary, our studies will contribute more broadly to our understanding of the membrane trafficking steps involved during a normal cell-mediated immune response, establish common and gene-specific pathways affected in wide range of genetic disorders that share some manifestations of HLH symptoms, aid in the development of new diagnostic tools and help in therapeutic decisions.
Rotational Projects (2016-2017):
Test how FHL mutations in STXBP2 and MUNC13-4 affect SNARE-mediated fusion using reconstituted fusion assays
Study the effect of FHL mutations on the perforin-dependent and cell death receptor-dependent killing pathways.
Investigate by Super Resolution Microscopy (STED) the distribution patterns of fluorescently labeled SNAREs during the cytotoxic immune response.
Waldo A. Spessott (Postdoctoral Fellow)
Margaret McCormick (Research Technician)
Maria L. Sanmillan (Research Technician)
Vineet V. Kulkarni (CPM- Graduate Student)
Cell and Molecular Biology
B.A.. (Biochemist), National University of Cordoba - Argentina, 1996
M.S. (Chemistry), National University of Cordoba - Argentina, 1997
Ph.D. (Chemical Sciences), National University of Cordoba - Argentina, 2002
Doctoral Fellow, Chemical Sciences, CIQUIBIC-CONICET, Centro de Investigaciones en Química Biologica, University of Cordoba - Argentina., 1998-2002
Postdoctoral Fellow, Biological Chemistry, CIQUIBIC-CONICET, Centro de Investigaciones en Química Biologica, National University of Cordoba - Argentina., 2002-2003
Postdoctoral Fellow, Cellular Biophysics and Biochemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA., 2003-2004
Postdoctoral Research Scientist, Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., 2004-2006
Awards and Honors
Doctoral Fellowship from Consejo de Investigaciones Cientificas y Tecnologicas de la Provincia de Cordoba, Argentina (CONICOR)., 1996
Doctoral Fellowship from Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (CONICET)., 1998
VI Bernardo A. Houssay Award of the Argentinean Society of Biology., 2000
Postdoctoral Fellowship from Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (CONICET)., 2002
PEW Scholar in Biomedical Sciences - The PEW Charitable Trusts, 2013
W.W. Smith Scholar / W.W. Smith Charitable Trust, 2015
Histiocyte Society Award / Histiocyte Society, 2016
Memberships and Professional Organizations
American Society of Cell Biology, 2003 - Present
Histiocyte Society, 2013 - Present
American Association for Immunologist, 2013 - Present
Familial hemophagocytic lymphohistiocytosis caused by a novel dominant-negative mutation in STXBP2 that inhibits SNARE-mediated membrane fusion
Waldo A. Spessott , Maria L. Sanmillan , Margaret E. McCormick , Nishant Patel , Joyce Villanueva, Kejian Zhang, Kim E. Nichols and Claudio G. Giraudo, Blood 125(10): 1566-77, 2015, PMID:25564401
Endogenous species of mammalian nonmuscle myosin IIA and IIB include activated monomers and heteropolymers
Maria Shutova, Waldo A. Spessott, Claudio G. Giraudo, Tatyana Svitkina, Current Biology 24(17): 1958-68, 2014, PMID:25131674
Antonny B, Audhya J, l Bagnat M, von Blume J, Briggs JA, Giraudo C, Kaeser PS, Miller E, Reinisch K, Sbalzarini IF, Schuldiner M, Shen J, Takamori S, Verstreken P, Walther T., Developmental Cell 27(5): 480-4, 2013, PMID:24482802
Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Syntaxin 1 H3 domain and SNARE complex.
Shi L, Kümmel D, Melia TJ, Coleman J, Giraudo CG, Mol. Biol. Cell 22(): 4150, 2011
A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion.
Krishnakumar SS, Radoff DT, Kümmel D, Giraudo CG, Li F, Khandan L, Baguley SW, Coleman J, Reinisch KM, Pincet F, Rothman JE, Nat Struct Mol Biol. 18(8): 934-40, 2011
Complexin cross-links prefusion SNAREs into a zigzag array.
Kümmel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM, Nat. Struct. Mol. Biol. 18(8): 927-33, 2011
Complexin activates and clamps SNAREpins by a common mechanism involving an intermediate energetic state
Li F, Pincet F, Perez E, Giraudo CG, Tareste D, Rothman JE, Nat Struct Mol Biol. 18(8): 941-6, 2011
Identificatification of a site in Sar1 involved in the interaction with the Cts of Glycolipid Glycosyltransferases.
Quinteros CA, Giraudo CG, Villareal M, Montich G and Maccioni HJ, J. Biol. Chem 285(): 30340-6, 2010
Alternative zippering as an On-Off switch of SNARE-mediated membrane fusion.
Giraudo CG, Garcia-Diaz A, Eng WS, Chen Y, Hendrickson W, Melia TJ, Rothman JE, Science 323(): 21211-21219, 2009
Distinct domains of complexins bind SNARE complexes and clamp fusion in vitro
Giraudo CG, Garcia-Diaz A, Eng WS, Yamamoto A, Melia TJ, Rothman JE, J Biol Chem 283(): 21211-21219, 2008