Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics (2006)

NEW DIRECTIONS IN THE STUDY OF ANTIMICROBIAL THERAPEUTICS: IMMUNOMODULATION

April 28-29, 2005

Keck Center of the National Academies • Rooms 201 and 109

500 Fifth Street, N.W. • Washington, D.C. 20001

Thursday, April 28, 2005 (Room 201)

Friday, April 29, 2005 (Room 109)

1. Intervention strategies in adaptive immunity

2. Intervention strategies boosting innate immunity

3. Intervention strategies based on damage control

4. Intervention strategies based on interactions of normal microbiota with host

• Lorne A. Babiuk, University of Saskatchewan

• Jacques Banchereau, Baylor University

• Christine A. Biron, Brown University

• Arturo Casadevall, Albert Einstein College of Medicine (chair of committee)

• Yung-Chi “Tommy” Cheng, Yale University

• Rita R. Colwell, University of Maryland, Johns Hopkins University, and Canon U.S. Life Sciences (member of committee)

• John E. “Jack” Edwards, Jr., David Geffen School of Medicine at UCLA and Harbor-UCLA Medical Center

• R. Alan B. Ezekowitz, Harvard Medical School and Massachusetts General Hospital

• Danielle A. Garsin, University of Texas Health Science Center at Houston

• R.E.W. (Bob) Hancock, University of British Columbia (member of committee)

• Katherine Knight, Loyola University Chicago Stritch School of Medicine

• Arthur M. Krieg, Coley Pharmaceutical Group, Inc.

• Philip O. Livingston, Memorial Sloan-Kettering Cancer Center

• Elias Lolis, Yale University

• Richard Malley, Harvard Medical School and Children’s Hospital Boston

• Jennifer Maynard, University of Minnesota

• Margaret Jean McFall-Ngai, University of Wisconsin-Madison (member of committee)

• Francis Michon, BioVeris Corporation

• Cathryn Nagler-Anderson, Harvard Medical School and Massachusetts General Hospital

• Carl Nathan, Weill Medical College of Cornell University (member of committee)

• Kenneth H. Nealson, University of Southern California

• William Paul, National Institute of Allergy and Infectious Diseases, NIH

• Liise-anne Pirofski, Albert Einstein College of Medicine (member of committee)

• Jane Salmon, Weill Medical College of Cornell University and Hospital for Special Surgery

• Monisha G. Scott, Inimex Pharmaceuticals

• Alan Sher, National Institute of Allergy and Infectious Diseases, NIH

• Brad Spellberg, David Geffen School of Medicine at UCLA and Harbor-UCLA Medical Center

• Roland K. Strong, Fred Hutchinson Cancer Research Center

• Kevin J. Tracey, North Shore-LIJ Research Institute and Albert Einstein College of Medicine

• Elaine Tuomanen, St. Jude Children’s Research Hospital

• Arthur Tzianabos, Harvard Medical School (member of committee)

• Aaron Weinberg, Case Western Reserve University

• Dennis M. Zaller, Merck Research Laboratories (member of committee)

• Petr Bocek (immunology)

• Susan A. Daniels (microbiology)

• Alison Deckhut Augustine (immunology)

• Michael Kurilla (biodefense)

• Marshall Plaut (immunology)

• Gyan (John) Prakash (regulatory affairs)

• David Winter (immunology)

• Adam P. Fagen, Program Officer

• Joe Larsen, Postdoctoral Research Associate

• Matthew McDonough, Program Assistant

• Ann Reid, Program Officer

• Fran Sharples, Director, Board on Life Sciences

John E. “Jack” Edwards, Jr., is Chief of Infectious Diseases at the Harbor/ UCLA Medical Center and Professor of Medicine at the David Geffen School of Medicine at UCLA. His research interests are in fungal infections in immunocompromised hosts, with a focus on disseminated candidiasis. The investigators in his group are engaged in projects related to novel ways of treating infections. They include the use of synthetic peptides, context activated peptides, the infusion of activated phagocytes in neutropenic patients, and manipulation of host iron levels during infection. Dr. Edwards is currently engaged in preclinical studies to develop a vaccine using a recombinant protein known to be an adhesion for Candida to human cells. This vaccine is targeted primarily for short-term use in intensive care patients and eventually in immunocompromised hosts. Dr. Edwards is also the past chairman of the Public Policy Committee of the Infectious Diseases Society of America (IDSA) and currently a member of the Antimicrobial Availability Task Force of the IDSA, which is proactively addressing the lack of development of new antiinfectives within large pharmaceutical companies. Current positions also include being the Chairman of the FDA Antiinfective Advisory Committee and a member of the Board of Scientific Councilors of the Clinical Center at NIH.

R. Alan B. Ezekowitz is The Charles Wilder Professor of Pediatrics at Harvard Medical School, Chief of the Pediatric Service as Massachusetts General Hospital, Chief of the MassGeneral Hospital for Children, and Chief of the Pediatric Service for Partners HealthCare System in Boston. He earned a D.Phil. from the University of Oxford and an M.B.Ch.B. from the University of Cape Town and has previously held appointments at the Dana Farber Cancer Institute and Children’s Hospital in Boston. He serves on the Board of the Society for Leukocyte Biology, the Editorial Board on Microbes and Infection, and chaired the 2002 Keystone Symposium on “Innate Immunity: Evolution and Link to Adaptive Immunity.” Dr. Ezekowitz chairs the Scientific Advisory Committee for Anika Therapeutics, serves on the Board of NatImmune and on the scientific advisory committees of EntoMed and Codman. Major research interests include pattern recognition molecules in innate immunity, immunodeficiency, and vascular tumors of infancy. His laboratory has focused on examining how the innate immune system distinguishes species self from nonself in both mammalian systems and insects. From mammalian systems, he has learned that subtle variations in pattern recognition molecules, like the mannose-

binding lectin (MBL) appear to alter the balance between the host and the infectious agents. In insects, the focus of the laboratory has been to explore the mechanisms of phagocytosis using Drosophila melanogaster as a model system.

Arthur M. Krieg is Chief Scientific Officer, Senior Vice President for Research and Development, and co-founder, Coley Pharmaceutical Group. He discovered the CpG motif in 1994, and co-founded Coley Pharmaceutical Group in 1997. In addition to responsibility for internal Coley R&D, Dr. Krieg coordinates collaborative research programs with numerous other academic groups as well as corporate partners including Pfizer and sanofiaventis. Dr. Krieg is also the Principal Investigator for $35 million in sponsored research programs on CpG technology with NIAID and the Defense Advanced Research Projects Agency.

Dr. Krieg graduated from Haverford College in 1979, received his M.D. from Washington University in 1983, and completed a residency in Internal Medicine at the University of Minnesota in 1986. He was a Staff Fellow at the NIH in the Arthritis Institute from 1986 to 1991, when he left to become an Assistant Professor in the Department of Internal Medicine at the University of Iowa. He was promoted to full Professor in 1998, and has been on a leave of absence from the University since 2001, when he joined Coley full-time. Dr. Krieg is co-founder and co-Editor of the journal Oligonucleotides, and is on several other editorial boards. Dr. Krieg is a board-certified rheumatologist and a Fellow of the American College of Rheumatology. He has published more than 200 scientific papers and is co-inventor on 10 issued U.S. patents covering CpG oligos. His 1995 Nature paper reporting the discovery of the CpG motif has been cited more than 1200 times.

Margaret Jean McFall-Ngai received her Ph.D. in Biology from UCLA in 1983. Following postdoctoral positions in protein biochemistry at UCLA Medical School and UC San Diego, she held a faculty position at University of Southern California, where she was awarded tenure in 1994. In 1996, she moved to the University of Hawaii, Manoa, to the Pacific Biomedical Research Center, and then on to a professorship in the Department of Medical Microbiology and Immunology at the University of Wisconsin-Madison in June 2004. Her laboratory studies the influence of beneficial bacteria on health and disease using the squid-vibrio animal model system, the development of which she has pioneered with colleagues in microbiology.

Liise-anne Pirofski is a Professor of Medicine and Microbiology and Immunology at the Albert Einstein College of Medicine. She received her B.A. from the University of California at Berkeley and her M.D. from Albert Einstein College of Medicine. After residency in Internal Medicine at Bellevue Hospital and the NYU Medical Center and fellowship training in Infectious Diseases at the Albert Einstein College of Medicine and Montefiore Medical Center, she did a postdoctoral fellowship in immunology in the laboratory of Matthew Scharff. She is currently a member of the Host Interactions with Bacterial Pathogens review panel of NIAID, an Associate Editor of Medical Mycology, and involved in medical education as course director of the Microbiology and Infectious Diseases course at the Albert Einstein College of Medicine. Her research program is focused on immunity to encapsulated pathogens, using Cryptococcus neoformans and Streptococcus pneumoniae as examples, and the interplay between the status of the antibody repertoire and microbial factors in the pathogenesis of these microbes in immunocompromised persons. She has also written numerous reviews developing useful models for the understanding of complex issues such as the bioweapons potential of microbes, a novel damage-response model of microbial pathogenesis, and the history and future potential of antibody and vaccine based immune therapeutics.

Kevin J. Tracey is Professor and Head of the Center for Patient Oriented Research at the North Shore-LIJ Research Institute, Manhasset, NY, Program Director of the General Clinical Research Center (GCRC), and Professor of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY. He received a B.S. from Boston College, an M.D. from Boston University, and completed clinical training in neurosurgery at the New York Hospital-Cornell University Medical College. Since 1992 he has been at the North Shore-LIJ Research Institute, directing a laboratory that focuses on cytokine biology in disease pathogenesis. With his colleagues, Dr. Tracey discovered the cytokine activity of HMGB1, a protein known previously only as a transcription factor, and demonstrated that HMGB1 is an experimental therapeutic target for sepsis and arthritis. With his colleagues, he also discovered that the neural output of the vagus nerve can regulate the magnitude of the innate immune response to infection and threat. Based on this work, clinical testing of anti-HMGB1 antibodies, and specific cholinergic agonists, is anticipated to begin in 2006-7, sponsored by a biotech company (Critical Therapeutics, Inc.) that Dr. Tracey co-founded in 2000.