Faculty

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John Treanor, M.D.
David Topham, Ph.D.
Andrea J. Sant, Ph.D.
Gary Whittaker
Toru Takimoto DVM, Ph.D.
Mark Y. Sangster, Ph.D.

John Treanor, M.D.

Professor of Medicine and Professor of Microbiology and Immunology
Department of Medicine
Division of Infectious Diseases
Human immune responses to influenza virus, and clinical vaccine trials

He is the Principal Investigator and Director of the University of Rochester Vaccine and Treatment Evaluation Unit (VTEU). Recent studies have included evaluation of live attenuated influenza vaccines in infants and young children, evaluation of smallpox, anthrax and genital herpes vaccines in healthy adults, and evaluation of novel inactivated influenza vaccines and of protein-conjugate pneumococcal vaccines in ambulatory elderly adults. In collaboration with Ed Walsh and Ann Falsey, the unit also evaluates the immune response to respiratory syncytial virus (RSV) in adults using a recently described human infection model. Dr. Treanor has a long standing interest in influenza pathogenesis and vaccine development. He has collaborations with Dr. Eun-Hyung Lee and Timothy Mosmann in studies evaluating aging and the immune response to influenza vaccine, with Dr. Xi Jin on the effect of lipid supplementation on influenza vaccine responses in the elderly, and with Dr. Jan Moynihan on the effects of stress on influenza immune responses in elderly residents of nursing homes.

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David Topham, Ph.D.

Associate Professor of Microbiology and Immunology
David H Smith Center for Vaccine Biology and Immunology
T cell responses to influenza virus infection

The specter of a pandemic caused by avian influenza virus highlights the need to identify possible mechanisms of immune protection from emerging strains of the flu virus. We cannot accurately predict which influenza will emerge as the next pandemic, making it difficult to select and manufacture sufficient conventional vaccine to elicit protective homotypic antibodies. Protective T cell mediated heterosubtypic immunity to influenza is an established paradigm in animal models, but is not well documented in humans. Though it is likely that heterosubtypic immunity to influenza exists in humans, there is little evidence of its specificity, and the reasons why it may or may not be protective are unclear. Our lab has shown that optimal CD8 T cell mediated heterosubtypic immunity is provided when T cells are retained in the lung tissue and airways via their interaction with collagen via the VLA-1 collagen receptor (Ray et al., 2004). One hypothesis is that heterosubtypic immunity to influenza fails in humans because of insufficient memory in the lung tissue. Having these T cells in place would not prevent infection, but could limit the duration and magnitude of viral replication. This could be the difference between life and death when encountering an emerging pandemic strain of influenza. Conventional influenza subunit vaccination is designed to generate antibodies, and does not strongly stimulate tissue-memory. Future strategies for influenza vaccine design should target both antibodies and cross-reactive lymphoid and tissue memory T cells. Our goals are to better understand potentially heterosubtypic immune responses to influenza and begin to develop the means to evaluate and, in the future, promote optimal vaccination strategies. To accomplish these goals, the Topham lab has established assays for detailed analysis of cell-mediated immunity (CMI) against influenza in humans, and has developed improved animal models for studying CD4 T cell mediated influenza immunity in mice. Comprehensive assay systems are established to target CD4 and CD8 T cells, and B cells responding to influenza virus, viral hemagglutinin, or influenza vaccines.

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Andrea J. Sant, Ph.D.

Professor of Microbiology and Immunology
David H Smith Center for Vaccine Biology and Immunology
Immunodominance of CD4 T cell responses to influenza virus

Dr. Sant is funded by NIAID to develop and implement stragies to elucidate the molecular mechanisms that control immunodominance in CD4 T cell responses to forgeign antigens. Dr. Sant's laboratory has developed expertise in epitope identification and T cell ELISPOT assays to quantify CD4 T cell responses as well as biochemical assays to elucidate the critical features of peptide:MHC class II interactions that regulate the ability of those complexes to elicit CD4 T cell responses in vivo. Because of the striking findings made thus far in these studies, Dr. Sant has recently been funded by a R21 award to initiate studies of human T cell responses to influenza.

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Gary Whittaker

Associate Professor of Virology
Cornell University
The mechanism by which influenza viruses, rhaboviruses and coronaviruses enter into host cells

The molecular determinants and related mechanisms that make certain influenza viruses highly pathogenic for mammalian species, including humans, remain poorly understood. Both viral factors and host factors may determine virulence. Some studies, however, suggest that mutations in viral polymerase proteins play a major role in adaptation to mammalian species, such as humans, mice and ferrets. A reverse genetics study revealed that the amino acid at position 627 of PB2, a subunit protein of the viral RNA polymerase, determines the efficiency of virus replication in mice. Mutation at PB2 627 alone, however, does not explain the pathogenicity of some avian H5N1 viruses isolated from humans, suggesting that other, as yet undefined, amino acid differences are likely to contribute to virulence in mammals. Other polymerase genes also probably influence host specificity. We will determine the role of the polymerase in avian virus adaptation to mammalian hosts. Polymerase components and residues, which enhance polymerase activity in mammalian hosts will be identified, and their role in pathogenicity will be determined using rescued mutant viruses. Characterization of avian and human virus polymerase activities, as well as identification of the responsible residues will ascertain the role of polymerase proteins in adaptation to mammalian hosts.

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Toru Takimoto, DVM, Ph.D.

Assistant Professor of Microbiology and Immunology
Influenza virus determinants of host adaptation

The introduction and subsequent spread in the human population of Influenza A virus with novel hemagglutinin (HA) and neuraminidase (NA) subtypes is a serious threat to human health because of the lack of immunity against these viruses. Recent human fatal infections caused by highly pathogenic avian influenza A viruses (H5N1) highlighted the continuous threat of new pathogenic influenza viruses emerging from a natural reservoir in birds. The molecular determinants and related mechanisms that make certain influenza viruses highly pathogenic for mammalian species, including humans, remain poorly understood, although recent evidence has suggested that the viral polymerase proteins play a key role in this process. In my lab, we are studying the role of polymerase and matrix proteins in host adaptation of influenza A viruses. Using a reverse genetics system, we are analyzing mutations and molecular mechanisms associated with viral adaptation to mammalian hosts. Our goal is to reveal the molecular basis of mammalian host adaptation of avian influenza A viruses.

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Mark Y. Sangster, Ph.D

Research Associate Professor
David H Smith Center for Vaccine Biology and Immunology

Virus-specific antibodies play a key role in providing a protective barrier to infection and in facilitating viral clearance once an infection is established. Antibody-producing cells or plasma cells are generated from B cells that divide and differentiate following recognition of specific antigen. A critical requirement for optimal antibody responses is the cognate help delivered to activated B cells by CD4 T cells.

This help is important for directing antibody isotype switching in B cells, the process by which B cells switch from expressing IgM to expressing alternative isotypes (such as IgG1, IgG2a, and IgA in the mouse) with different functional characteristics. In addition, cognate T cell help is critical if activated B cells are to participate in germinal center reactions, where affinity maturation of the antibody response takes place and the cellular elements of B cell memory are generated. These elements include long-lived plasma cells, which maintain high levels of protective antibodies, and a population of memory B cells that will respond with rapid antibody production on re-exposure to cognate antigen. This brief overview grossly simplifies a remarkable and complex process that is regulated at many levels in ways that modulate the kinetics, magnitude, and quality of the acute B cell response, as well as characteristics of dispersed plasma cell and memory B cell populations. In general terms, our research is aimed at understanding the characteristics of optimally effective B cell responses and applying this knowledge towards the improvement of vaccination regimens.
Specific Research Interests:
Our specific research focus is the B cell response to viruses that infect the respiratory tract (with an emphasis on influenza virus) and to vaccination regimens designed to generate B cell-mediated protection against these viruses. Particular research interests include: (i) regulation of the acute B cell response to infection and vaccination and the differentiation pathways that generate B cell memory and virus-neutralizing antibodies, (ii) aspects of B cell memory (plasma cells, memory B cells) in the respiratory tract, including mechanisms of localization, role in protection, and relationship to form of immunization, and (iii) regulation of IgA production and the establishment of antibody-mediated protection at mucosal surfaces.

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Get in Touch

For general questions, call:
Donna Neu
(585) 276-5621

Email: Donna Neu

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