Thomas Moran, PhD (PI of the Center, the Technology Development Component , the Education and the Administrative Core) Dr. Moran is a Professor of Microbiology and Immunobiology at Mount Sinai School of Medicine. For the past 10 years his work has focused on the immune responses generated to respiratory virus infection with a particular emphasis on influenza virus. Early work from Dr. Moran and his colleagues investigated the effect of cytokines that directed immune responses in a Th1 (IL-12) or a Th2 (IL-4) direction on recovery from influenza virus infection in a mouse model. The Th1 cytokine had no effect on the response but IL-4 profoundly inhibited cellular immunity, and the mice failed to clear virus from their lungs. The demonstration of enhanced pathogenicity of a chimeric mouse poxvirus carrying the IL-4 gene later confirmed these observations and demonstrated the potential danger of such a virus.  Investigations into Th1/Th2 polarity in response to live and inactivated virus vaccines, document a failure of inactivated virus to trigger Th1 immunity. The discovery suggested that inactivated virus might not be capable of fully inducing dendritic cell activation an observation that was confirmed using in vitro grown DCs. The observation that inactivated virus neither triggered maturation nor release of interferon from myeloid DCs led to investigations into the relationship of the interferon pathway with initiation of adaptive immunity, a dominant theme in this center. Using unique methods in vivo, analysis of dendritic cell migration, maturation and T cell activation was reported in a recent collaboration with Ralph Steinman at Rockefeller University. In this study it was demonstrated that while antigens are presented by DCs in all instances they effectively activate T cells only if they have received a maturation signal such as a live influenza virus infection. Recently they have shown that virus triggered myeloid DC maturation does not occur through a toll like receptor but by an intracellular route related to the interferon pathway. Dr. Moran is on the editorial board of the Journal of Virology, and a frequent reviewer for Journal of Experimental Medicine and Journal of Immunology. He is a member of the Viral Therapeutics and Pathogenesis of the North East Biodefense Center proposal that was recently funded by NIAID.  He serves on two study sections; Special Emphasis Panel: Biodefense Partnerships and Small Business and Technological Applications ZRG1 SSS-4 10 B. He has over 70 publications in peer-reviewed journals and a number of book chapters including a recent chapter on dendritic cells and tuberculosis. He serves as the course director for the Medical microbiology/immunology course.
	Peter Palese, Ph.D. (Project 1 Principal Investigator) Dr. Palese is interested in the replication of RNA-containing viruses, and in understanding viral pathogenicity and virus-host interactions.  He has placed a special emphasis on influenza viruses, parainfluenza viruses (including Newcastle disease viruses) and more recently Nipah viruses; all of these viruses are negative-strand RNA viruses. In addition, Dr. Palese has been studying the molecular biology of corona viruses and has started a program on analyzing the structure/function relationship of SARS virus proteins.  The Palese laboratory established the first genetic maps for influenza A, B and C viruses, identifying the genes coding for specific viral proteins.  His laboratory was first to define the function of the neuraminidase gene and to determine the mechanism of action of neuraminidase inhibitors in the cell; two FDA-approved antiviral drugs are based on this principle.  Another major achievement of the laboratory was the development of reverse genetics techniques for negative-strand RNA viruses, which allowed the genetic engineering of these viruses.  Such techniques have made it possible to do detailed structure-function studies of specific viral genes.  In the future, genetically engineered negative-strand RNA viruses may be used as vaccines in humans and animals.  Dr. Palese is a member of the National Academy of Science, he currently serves on the FDA Advisory Panel for Biologicals and Vaccines, he is an Editor for the Journal of Virology and he serves on the Editorial Board for PNAS.
	Christopher F. Basler, Ph.D. (Project 2 Principal Investigator) Dr. Basler is Assistant Professor in the Department of Microbiology at the Mount Sinai School of Medicine.  He received extensive research training in the molecular biology of viruses, having done his PhD work on the molecular biology of adenoviruses. Since the completion of his Ph.D studies he has concentrated on the molecular biology of negative-strand RNA viruses, in particular on Ebola viruses, Nipah virus and influenza virus. Dr. Basler has developed novel assays designed to identify viral proteins that counteract the host interferon response and has used these assays to identify and Ebola virus “interferon-antagonist” protein, VP35, and Nipah virus interferon antagonists.   The focus of Dr. Basler’s CIVIA project is the Ebola virus VP35 protein.  He has previously demonstrated that VP35 can functionally substitute for another viral “IFN-antagonist,’ the influenza A virus NS1 protein and can inhibit production of IFN induced by several stimuli, including either Sendai virus infection or dsRNA transfection. Inhibition of host IFN responses appears to occur, at least in part, because VP35 can prevent the phosphorylation that leads to the activation of interferon regulatory factor 3 (IRF-3), a cellular transcription factor that plays a critical role in the virus-mediated activation of IFN gene expression. Consistent with these observations, EBOV infection does not activate IRF-3. Subsequently studies have demonstrated an ability of VP35 to antagonize several pathways that lead to IRF-3 activation.  Given reports that Ebola virus infection suppresses dendritic cell (DC) maturation and the work of Dr. Moran indicating that the degree to which a virus activates interferon responses influences DC maturation, Dr. Basler will explore the impact of VP35 expression on human DCs and, with the assistance of collaborators with BSL4 laboratories, compare these results with the impact of Ebola infection on DCs.
	Adolfo García-Sastre, Ph.D. (Project 3 and Pilot Project component Principal Investigator, Technology Development Component co-Investigator). Dr. García-Sastre is Professor in the Department of Microbiology of Mount Sinai School of Medicine in New York.   For the past 15 years, his research interest has been focused on the molecular biology of influenza viruses and several other negative strand RNA viruses.  During his post-doctoral training in the early 1990s, he developed, for the first time, novel strategies for expression of foreign antigens by a negative strand RNA virus, influenza virus. He has made major contributions to the influenza virus field, including 1) the development of reverse genetics techniques allowing the generation of recombinant influenza viruses from plasmid DNA, (studies in collaboration with Dr. Palese); 2) the generation and evaluation of influenza virus vectors as potential vaccine candidates against different infectious diseases, including malaria and AIDS, and 3) the identification of the biological role of the non structural protein NS1 of influenza virus during infection: the inhibition of the type I interferon (IFN) system.  His studies provided the first description and molecular analysis of a viral-encoded IFN antagonist among negative strand RNA viruses.  These studies led to the generation of attenuated influenza viruses containing defined mutations in their IFN antagonist protein that might prove to be optimal live vaccines against influenza. His research has resulted in more than 100 scientific publications and reviews. Together with Charlie Rice, he is the leader of the basic research component on Viral Therapeutics and Pathogenesis of the North East Biodefense Center proposal, which was recently funded by NIAID and involves the collaboration of more than 20 academic institutions in New York, Connecticut and New Jersey.  He is among the first members of the Vaccine Study Section of the NIH. In addition, he is member of the Editorial Board of Journal of Virology, Virology, Journal of General Virology and Virus Research.  He has been a co-organizer of the international course on Viral Vectors (2001), held in Heidelberg, Germany, sponsored by Federation of European Biochemical Societies (FEBS), and of the first Research Conference on Orthomyxoviruses in 2001, held in Teixel, The Netherlands, sponsored by the European Scientific Working Group on Influenza (ESWI). His expertise on the mechanisms of evasion of innate immunity by negative strand RNA viruses, on the molecular biology of influenza viruses and on reverse genetics techniques to study viral gene function will be used to perform the studies delineated in project 3.
	James Wetmur, Ph.D. (Clinical/Epidemiology Core B co-Principal Investigator, Technology Development Component co-Investigator) Dr. Wetmur is a Professor of Microbiology and Human Genetics. He directs the allelic imbalance studies, one of the specific aims of the Technology Development Component (TDC) of the Center. Dr. Wetmur has extensive experience with nucleic acid technology development, especially in the field of hybridization. He holds seven issued U.S. patents in this field, and has served on numerous NIH study sections, including the Genome Study Section. In recent work related to single cell analyses, he has developed a single molecule-based molecular haplotyping system. The system begins with simultaneous PCR across two heterozygous polymorphic sites on single template molecules isolated by an oil-water emulsion. The method relies on linking PCR in the emulsion to connect the two PCR products, capping and allele-specific PCR readouts. Human PON1 haplotypes were determined in a large cohort to demonstrate haplotype-phenotype association. His laboratory is also applying emulsion technology for the selection of single bacterial clones expressing mutant thermostable DNA polymerases and accessory proteins. In the past they have studied thermostable mismatch repair proteins, assembled the complete downstream in vitro recombination system from Thermotoga maritima and investigated the properties of Methanococcus jannaschii flap endonuclease. Dr. Wetmur has been active in molecular epidemiology since the 1980's, beginning with his discovery of the role of a delta-aminolevulinate dehydratase genetic polymorphism in sensitivity to lead exposure, and now acts as the project director of the genetic component of the Mount Sinai Childrens’ Environmental Health Center, where his work has uncovered a genetic-based hypersensitivity of certain neonates to organophosphate pesticide exposure. In the current work in the Technology Development Component (TDC) of the Center, his laboratory is developing high-throughput methods for measuring mRNA allelic imbalance in human dendritic cells challenged with NDV, including analyses in single cells. These studies are expected to complement the transcriptome approach in the TDC and enable the discovery of new human variation evident only in the context of viral challenge. Such variation may be important in identification of susceptible individuals and in the development of vaccines.
	Stuart Sealfon, M.D.  (Technology Development Component co-Principal Investigator) Dr. Sealfon is the Saunders Professor and Director of Research in the Department of Neurology at Mount Sinai, has joint appointments as Professor in the Departments of Neurobiology and Pharmacology and Biological Chemistry, and directs a postdoctoral fellow training program. A board certified neurologist, he is a full time researcher interested in the molecular mechanisms of cellular signaling specificity.  He has an international reputation in the fields of G-protein coupled receptor structure function, signal transduction and genomics. He holds several patents and his laboratory is recognized for creative approaches to translational research.  He served on the scientific advisory board of Alanex Pharmaceuticals.  His laboratory has developed innovative genomics-based approaches to study signal transduction that are being productively applied to the characterization and quantification of immune cell responses to viral biopathogen exposure.
	Lloyd Mayer, M.D. (Technology Development Component co-Investigator) Dr. Mayer is the Dorothy and David Merksamer Professor of Medicine and Immunobiology and Chairmen of Immunobiology. He was recently appointed as Division Chief of Gastroenterology at Mount Sinai. He has spent his entire career studying human immune responses in the GI tract and he specializes in investigations into the mechanisms of inflammatory bowel disease. In order to study human GI responses, Dr. Mayer developed new and unique technology including extensive studies of nonclassical antigen presentation by cells in the epithelial lining of the intestinal tract. In order to explain mechanisms underlying the generally immunosuppressed tone of immune responses in the intestine, he has focused on the role of the intestinal epithelial cell in terms of its ability to act as an antigen presenting cell. Dr. Mayer previously demonstrated that normal intestinal epithelial cells express class II MHC antigens yet selectively activate CD8+ suppressor T cells in co-culture. Current research revolves around the cloning and functional characterization of a molecule expressed on normal epithelial cells, gp180, which binds to CD8 and activates a src-like tyrosine kinase (p56lck) within these suppressor T cells. Other studies include assessing the role of nonclassical MHC products (CD1d) expressed on epithelial cells in T cell activation and the effects of T cell derived cytokines on epithelial cell growth, differentiation, and APC function.
	Ana Fernandez-Sesma, Ph.D. (Pilot Project 1 Principal Investigator (2004-2006) and Technology Development Component co-Investigator) is an assistant professor in the Department of Microbiology at Mount Sinai School of Medicine. She has expertise in the field of viral immunology using animal and human models to study the initiation of antiviral immunity against RNA viruses.  While in Dr. Moran’s laboratory Dr. Fernandez-Sesma generated pertinent data for the U19 application that resulted in the funding of CIVIA. She has an extensive ongoing collaboration with the laboratories of Drs. Garcia-Sastre and Palese, which provide an important virology component for the development of immunological studies.   Dr. Fernandez-Sesma oversees and trains personnel for the experimental section of this center. She designs and oversees key experiments involving virus infection and isolation of different elements from the dendritic cells after treatment. She is an expert in the collection of all types of human dendritic cells and has extensive experience growing, generating and using viruses such as influenza, VSV, vaccinia, RSV, dengue and NDV.  In addition, Dr. Fernandez-Sesma was the PI of a CIVIA funded pilot project (2004-2006) that explored the interaction between human dendritic cells and Dengue Virus. At present Dr. Fernandez-Sesma’s laboratory continues to study the initiation and evasion of immunity by Dengue and other viruses using human immune cells isolated from blood in collaboration with Dr. Jorge Munoz-Jordan at the Centers for Disease Control (Dengue Branch) in Puerto Rico.
	Domenico Tortorella, Ph.D.  (Pilot Project 3 Principal Investigator and Technology Development Component co-Investigator) Dr. Tortorella is an Assistant Professor of Microbiology at Mount Sinai School of Medicine. Prior to being appointed an Assistant Professor in January 2003, he was an instructor at Harvard Medical School in the laboratory of Dr. Hidde Ploegh. During his post-doctoral training, Dr. Tortorella was interested in host-pathogen interaction more specifically the mechanisms of how viruses escape the immune system. The study of how viruses avoid immune detection continues to be a main focus of the laboratory at Mount Sinai School of Medicine. Selective pressure by the immune system on viruses has resulted in their ability to generate evasive tactics to prevent immune recognition and become latent within the host. The immune system is alerted to the presence of a viral pathogen through the presentation of viral protein fragments (antigenic peptides) by the major histocompatibility complex (MHC) class I molecules. The human cytomegalovirus (HCMV), a member of the herpes virus family, encodes proteins derived from the unique short (US) region of the HCMV genome (US2 and US11) that prevent the surface expression of class I molecules. HCMV US2 and US11 induce the transport of the MHC class I molecules from the endoplasmic reticulum to the cytoplasm where they are degraded by a large proteolytic complex called the proteasome. Dr. Tortorella has been a key investigator in deciphering the key steps of the degradation pathway of MHC class I heavy chains. In addition, he developed a high-throughput screening assay to identify a family of chemical compounds referred to as eerstatins that block the transport reaction. The laboratory continues to focus on the identification of cellular components involved in US2 and US11 mediated destruction of class I molecules. The experimental strategies applied to the characterization of HCMV induced down regulation of MHC class I molecules continues to be used to identify other possible viruses that modulate the adaptive branch of the immune system. Dr. Tortorella has 30 publications that include peer-reviewed journals and review articles. He participates in teaching a Medical Microbiology Course and is the director of Student Journal Club for graduate students.