Expertise - Faculty Research Interests

Mission Statement IInfectious pathogens still remain a major cause of human diseases, whereas defective or excessive immunity causes an array of many other disorders including cancer, autoimmune disease, and allergic disease. The Department of Medical Microbiology and Immunology at the University of Toledo is dedicated to the fight against these common disorders. Microbiology explores the relationships between microbial pathogens and their human hosts, and immunology studies the nature of host defense system against environmental insults. The Department contributes to the research mission of the University by advancing basic and translational research with the ultimate goal of developing innovative vaccines and therapeutics for infectious diseases, cancer, and inflammatory disorders caused by immune dysregulation. Cutting-edge technologies in biomedical science are provided through the Flow Cytometry Core Lab; Bioinformatics, enomics/Proteomics Core Lab, and BSL-3 Lab housed in the Department. The Department also contributes to the teaching mission of the University by educating medical and graduate students in basic principles of immunology, bacteriology, virology, and host-pathogen interaction. Moreover, the Department contributes to the service mission of the University by providing advanced expertise in microbiology and immunology and by promoting regional, state, national and international research programs concerning infectious diseases, inflammatory disorders, and graft rejection.

How You Can Help The Department has successfully competed for peer reviewed grant funding. The Medical Microbiology and Immunology Research Ventures Fund has been created to ensure that we continue our record of achievement. The Fund will support innovative, high-risk research projects, and faculty will use these start-up grants to prove their hypotheses and position themselves to attract NIH and other peer-reviewed funding. This is an investment in the Department's future and in creative new approaches to discovering the causes of and treatments for immunologic disease. To make your contribution please contact Howard Newman, Associate Vice President for Development, Health Science Campus at 419.383.6840.

Recirculating T lymphocytes, recognizing their specific antigens on the surface of antigen-presenting cells, exert most adaptive immune and autoimmune responses. My research is focused on identifying the molecular mechanisms that regulate activation, differentiation, apoptosis, and tolerance in T lymphocytes. My current project aims at identification of “unique cytokine milieu” required for the generation of memory T (antigen-experienced T cells that persist long-term) versus CD4+CD25+Foxp3+ regulatory T cells (maintaining self-tolerance and suppressing various immune responses). The results of these studies will lead us to the development of novel therapeutic strategies for preventing T cell-mediated transplant rejection, autoimmune diseases (e.g., type 1 diabetes), and other immune disorders.

Our research focuses on defining viral and host factors essential for alphaviruses to replicate and cause inflammation of the brain. These enveloped, RNA viruses are transmitted by mosquitoes to birds and mammalian hosts, and are related to rubella viruses that are spread person-to-person and not by insect bite. The longrange
goal is to investigate the mechanisms by which rubella and alphaviruses replicate and control host responses determining infection outcome, i.e., persistence, cell death or curing of the infection. Other studies focus on the replication requirements of coronaviruses (common cold, SARS). Our work has been published in the Journal of Virology, and PlosPathogen, and has been funded through the National Institutes of Health.

Today, more people worldwide die from infectious diseases than of any other single cause. Tumor necrosis factor alpha (TNFa) is considered one of the key inflammatory mediators during bacterial infection. This powerful protein, secreted mostly by human leukocytes such as monocytes/macrophages, acts as a host defense against bacterial infections. However, when TNFa levels rise too much, it can lead to inflammatory disorders. A wide variety of stimuli have been shown to induce the production of TNFa, but bacteria products. are considered major inducers during bacterial infections. To date, most research on the production of TNFa has been focused on understanding how TNFa is induced by a single bacterial product. We have found that production of TNFa occurs when leukocytes are exposed to multiple bacterial products, and our results indicate that the bacterial products regulate the production of TNFa in a synergistic manner. The control of inflammation is likely to be best understood on this level. This represents an important pathogenic phenomenon occurring during bacterial infection. Our experiments provide information that is both unique and potentially important, and will significantly expand and enhance our understanding of how inflammation is induced in vivo when multiple bacterial products are present simultaneously. A better understanding of TNFa could bring new insights into the regulation of inflammation and may suggest novel therapeutic strategies or targets to minimize host injury following bacterial
infection.

Our bodies possess a number of surfaces (e.g., skin and lung) that form essential barriers to prevent microbial invasion into deeper tissues. Microbes that traverse these initial barriers will immediately contact innate immune cells (e.g., macrophages, dendritic cells, and Langerhans cells) that reside in these peripheral tissues, and play an important role in initially recognizing these infectious agents and directing an appropriate immune response. Thus, these early interactions between resident immune cells and invading microbes represent a critical juncture in deciding whether the infectious agents will be cleared by the immune responses or will establish a persistent infection and disease development. Our lab is interested in identifying the mechanisms by which two different bacterial pathogens are able to evade these early immune responses, so that they might be targeted for curative treatments. Borrelia burgdorferi is a spirochetal
bacterium that is spread by tick-bite and causes Lyme disease throughout the U.S., Europe and Asia; Lyme disease is the most prevalent anthropod-transmitted illness in these regions of the world. Burkholderia pseudomallei is a resilient soil-dwelling bacterium that is mainly found in tropical regions of the world and causes melioidosis. B. pseudomallei is designated as a select agent, in that it is extremely deadly when aerosolized, and can easily be used as a biological weapon. Our work has been published in the Journal of Immunology, Infection and Immunity, and the Journal of Clinical Investigation.

As an organ protecting the body from external insults, the skin is equipped with a tight physical barrier composed of terminally differentiated keratinocytes, as well as a highly sophisticated functional barrier. Langerhans cells are a skin-resident leukocyte subset known to play crucial roles in the latter barrier function by triggering protective immunity against infectious microbes, harmful chemicals, and cancer cells. Dysfunction of Langerhans cells, therefore, leads to a variety of disorders, including: infectious diseases (e.g., AIDS), autoimmune diseases (e.g., psoriasis), allergic diseases (e.g., contact dermatitis), and cancers (e.g., malignant melanoma). Our main objectives are to study molecular mechanisms regulating Langerhans cell development and function, and to develop a new class of immuno-therapeutics that are designed to control skin immune responses by altering Langerhans cell behaviors. Ongoing projects include: real-time in vivo imaging of Langerhans cells by combining two advanced technologies of gene knock-in mice and intravital confocal microscopy, identification of immediate progenitors for Langerhans cells using

My research is focused on inducing of long-term allograft survival (transplantation tolerance) and development of new immunosuppressive modalities. Activation of T lymphocytes requires three signals, with signal 3 (delivered by cytokines) regulating cell proliferation, differentiation, and survival/death. Cytokines binding to their receptors engage two molecular families, namely, Janus tyrosine kinases (Jaks) and signal transducers and activators of transcription (Stats). Among these signaling molecules, Jak3, Stat5 and Stat3 are investigated as potential targets for selective inhibition versus promotion of T regulatory cells and immature dendtritic cells to produce transplantation tolerance. Novel tyrosine (Y) phosphorylation sites (Y905 and Y935) are investigating on Jak3 and their role in T cell function. Similarly, Stat3 and Stat5 are investigated for differentiation of T cells into T helper 17 and T regulatory cells. Selective inhibitors of these molecules are being searched to promote apoptosis of T effector cells vs expansion of T regulatory cells. My research is supported by NIH grant and Novartis and Icagen funds. The work has been published in the Journal of Immunology, Blood, and Transplantation.

We are interested in the signaling pathways used by white blood cells that result in the killing of infectious agents. White blood cells are the first to the site of infection and induce potent antibacterial/antiviral responses coupled with induction of inflammation, all in the hope of clearing the infection. Fascinatingly, the pathways used to induce inflammation during infection are nearly identical to those resulting in such autoimmune diseases as Rheumatoid Arthritis and Systemic Lupus Erythematosus, both of which are caused by white blood cells. Therefore, targeted
therapeutics that enhance bacterial/viral killing but decrease inflammation would be beneficial to RA or SLE patients. To do this, we work on identifying mutual signal pathways between pathogen killing and inflammation. Our aim is to discover how these pathways can be enhanced or tempered, depending on the desired result. We use progressive technology to determine the role of antigen composition, membrane structure, and intracellular signaling networks. Understanding these signaling networks will lead us to the development of novel therapeutic targets to modulate inflammatory responses in the treatment of RA, SLE and infectious disease.

Dr. Collins’ research interest is in the translation of cellular therapies from the research laboratory into clinical application primarily in the setting of hematopoietic stem cell transplantation. Working with bone marrow, peripheral blood stem cells, and cord blood cells, her laboratory at Memorial Sloan-Kettering Cancer Center developed various methods to improve the safety and efficacy of hematopoietic cell transplantation and treatment of post-transplant complications. Dr. Collins founded professional organizations in cellular therapy, helped establish professional standards, and helped develop programs to accredit cellular therapy programs. She is currently chair of the Standards Committee for the Foundation for Cellular Therapy, and is working with he Alliance for Paired Donation, an organization that is applying a new model for living kidney donor transplantation. Dr. Collins also organized the UTHSC Women’s Programs Initiative that is charged with encouraging and developing programs to serve the needs of women at UT Health Science Campus.

Our laboratory has two components. One, funded by the National Science Foundation, focuses on gene exchange between bacteria (a source of virulence factors and antibiotic resistance genes), and the role played by restrictionmodification systems in modulating this exchange. The second, funded by the National Institutes of Health, focuses on how gene regulation (including control of virulence) evolves, and how it can be predicted from DNA sequences. This work has been published in journals such as the Journal of Bacteriology, Nucleic Acids Research, BMC Microbiology, and Proceedings of the National Academy of Sciences.

Our research We study the rules governing the evolution of RNA viruses using VSV as a model for human pathogens such as HIV, influenza and others. We have NIH support to analyze how viruses and environment interact to result in survival or extinction, so we can design better antiviral strategies. Our work has been published in the Journal of Virology and Journal of Molecular Biology.

The scope of our work includes the rapid identification and analysis of in fungi causing both infections of skin and deeper organs, including lungs and kidneys (the latter occur in cancer patients and persons receiving drugs interfering with immunity). The mechanisms used by skin-infecting fungi to generate useful products from hair and feathers in agricultural waste is a new area of research. Our work has been published in Infection and Immunity, Journal of Clinical Microbiology, and International Journal of Systematic Bacteriology. Current funding is through internal funds from The University of Toledo. Past funding includes: NIH (NIAID), American Heart Association, and Pfizer-Roerig.