Faculty

Jump To Faculty Profile

John Treanor, M.D.
David Topham, Ph.D.
Andrea J. Sant, Ph.D.
Tim Mosmann, Ph.D.
Gary Whittaker
Toru Takimoto DVM, Ph.D.
Kim Baek,
B. Paige Lawrence, Ph.D.
Jingming Ma

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.

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.

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.

Tim Mosmann, Ph.D.

Professor of Microbiology and Immunology
Director, David H Smith Center for Vaccine Biology and Immunology
T cell regulation of host responses to influenza virus infection

T cell cytokine-secreting subsets in influenza immunity require the measurement of T cell cytokine patterns, and so we have spent considerable effort on optimizing the detection of these patterns. The methods used for evaluation of cytokine secretion patterns of T cells have undergone considerable evolution, partly due to the availability of 18-color flow cytometry, and partly due to advances in the Luminex bead arrays. For direct determination of cytokine patterns in PBMC samples, the best method is currently intracellular staining and flow cytometry, because up to eight cytokines can be measured simultaneously, with concurrent detailed information on cell surface markers. Although this method only measures cytokines synthesized during a short window of secretion blockage, we have carefully tested the kinetics of influenza responses, and our current time of ten hours (the last eight hours with monensin and Brefeldin to block secretion) is suitable for IL-2, IFNgamma, IL-4, IL-5, TNFalpha, IL-10 and IL-13, and partly suitable for MIP-1beta.

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.

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.

Assistant Professor of Microbiology and Immunology

Role of avian flu RNA polymerase kinetics and fidelity in viral genomic mutagenesis, evolution and host species change: Genetic drift in influenza viruses is responsible for antigenic changes in hemagglutinin and neuraminidase proteins and is likely responsible for the ability of the current H5N1 avian influenza species to make the host species transition to humans, with fatal consequences. Genetic drift implicates the viral replication machinery as mechanistically involved in this process. The viral replication machinery must be capable of frequent mutation synthesis and massive viral replication in order to generate viral quasi-species capable of making this host specificity switch. Our laboratory has initiated a series of projects involving biochemical analysis and reverse genetic approaches aimed at understanding the involvement of avian influenza virus RNA polymerase kinetics and error rates in viral genetics and evolution.

B. Paige Lawrence, Ph.D.

Associate Professor, Department of Environmental Medicine

A major focus of our research is defining the molecular mechanisms by which pollutants adversely affect the immune response to respiratory infection. Specific focus is currently on the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) and the immune response to influenza A viruses. Dioxins bind and activate a receptor called the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor and is expressed in cells of the immune system and the lung. It is often considered an "orphan receptor," because it has been difficult to identify an endogenous ligand. However, in addition to dioxin, many other pollutants activate the AhR, including coplanar polychlorinated biphenyls (PCBs) and polyaromatic hydrocarbons (PAH), such as benzo[a]pyrene and 7,12-dimethylbenzanthracene, which are found in cigarette smoke and diesel exhaust. In addition to pollutants, many plant-derived natural compounds and tryptophan metabolites bind to the AhR. Therefore, we are exposed to AhR ligands daily through ingestion and inhalation.

It has been known for quite some time that dioxins are very potent immune suppressants, and that their toxicity is mediated by the AhR; however, the molecular mechanism is not known. Nevertheless epidemiological data suggest that exposure to pollutants that contain AhR agonists correlates with diminished host resistance, altered immune function and an increased incidence of influenza and other respiratory infections. In animals, AhR activation impairs survival following infection with influenza virus, further illustrating the relationship between exposure to AhR ligands and altered host resistance to infection.

Our specific focus is currently on defining the molecular mechanisms by which dioxin impairs the immune response to influenza virus infection. This work includes assessment of effects on innate and adaptive immune responses, and currently involves the following projects:

i. Elucidating the role of the AhR in pulmonary inflammation and determining the role of the AhR in dioxin-mediated impairment of host resistance to infection;
ii. Determining the mechanisms by which AhR activation impairs the activation, proliferation and differentiation of virus-specific T lymphocytes; and,
iii. Characterizing the effects of dioxin on immunological memory.

A separate but related project involves studies to understand how developmental exposure to dioxin causes functional alterations in the immune system of the offspring. The changes observed following exposure to dioxin during development include suppressed lymphocyte expansion and differentiation, altered cytokine production, and increased inflammation in the lungs after influenza virus infection. These changes in the immune response to infection occur at developmental exposures to dioxin that cause no detectable change in hematopoiesis or the cellularity of immune organs, suggesting that inappropriate AhR activation during development interferes with the normal programming of the immune system via epigenetic mechanisms.

Jingming Ma, Ph.D.

Assistant Professor - Department of Biostatistics and Computational Biology

The Data Management Core is developing a Web-based data management system for influenza research (FluRDM) for managing data and documents for New York Influenza Center of Excellence (NYICE). The scope of the FluRDM system has been extended to a comprehensive data management platform, which is not only providing the data management for immunological experiment data, but also providing the full data services for subject/samples, assay protocols, processed data, and miscellaneous documents. The FluRDM system will also provide an easy-access platform for sharing all data and documents involved in the large studies like NYICE. As planed in the proposal, the data management for major immunological assays like ELISPOT, ELISA and flow cytometry has already been in service. The current focuses are software development on the integration of clinical data (subject/sample) and experimental data.

Get In Touch

For general questions, call:
William Flesher
(585) 275-7856

Email: William Flesher