Immune system

David Baltrus (PhD) is broadly interested in understanding how bacterial evolution is shaped by interactions with other organisms. Questions investigated by the Baltrus lab range from asking how evolutionary events such as the transfer of genes between microbes affects the development of antibiotic resistance to testing how microbiomes impact the development and physiology of plants and animals. The lab approaches these questions by using a variety of existing tools, from screening for mutants using "toothpicks and agar plates" to experimental evolution to comparative genomics. However, Dr. Baltrus is also highly interested in developing new tools that enable sequencing and tracking of bacterial populations and communities of interest (like potential pathogens) in real time under natural conditions.

I am an Associate Professor in the department of Nutritional Sciences (College of Agriculture and Life Sciences) at the University of Arizona and hold joint appointments in Pediatrics (College of Medicine) and Immunobiology (College of Medicine). I am also part of the mentoring team for the Physiological Sciences and Cancer Biology Graduate Interdisciplinary Programs, which recruit students who are continuing in education. My research interests are concerned with the effects of aging, stress and exercise on the immune system, and the role of adrenergic receptor signaling on immune cell redistribution and activation. Major focus areas include understanding (1) how exercise and other behavioral interventions can offset age-related decrements in the normal functioning of the immune system (immunosenescence), (2) how adrenergic receptor signaling can be used to improve cellular products for hematopoietic stem cell transplantation and immunotherapy, (3) the interplay between the immune and neuroendocrine system during high level human performance and extreme isolation (i.e. space travel), and (3) how persistent virus infections such as cytomegalovirus (CMV) can alter the phenotype and function of T-cells and NK-cells to protect the host from certain hematological malignancies. My current research is supported by NASA, the NIH (National Cancer Institute) and industry. I am a fellow of the American College of Sports Medicine (ACSM) and an honorary board member of the International Society of Exercise Immunology (ISEI). I am an active member of the Pychoneuroimmunology Research Society (PNIRS) and the Society for Immunotherapy of Cancer (SITC) and sit on the editorial board of the following scientific journals: Brain, Behavior and Immunity; Exercise Immunology Reviews (Associate Editor); Immunity and Ageing; American Journal of Lifestyle Medicine.

The innate immune system has a large repertoire of receptors/sensors that respond to microbial components and host “danger signals” in order to regulate inflammation and immune responses. The dysregulation of many of these sensors has been linked to chronic inflammatory disorders (e.g., inflammatory bowel diseases) and multiple types of cancer. My group’s research focuses on how the dynamic relationship between the intestinal microbiota and these innate immune sensors regulate the cell signaling events driving chronic inflammation and cancer development. We seek to treat these diseases through the manipulation of intestinal microbial ecology and redirection of immune activation.

Dr. Viswanathan’s research efforts over the past 12 years have focused on the mechanisms of pathogenesis of the diarrheal disease pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC). His laboratory characterized EPEC and EHEC virulence factors (specifically those secreted into host cells) and evaluates their effect on host cell physiology including barrier function, cell death pathways, and effects on innate immune responses. His specialization is innate immune signaling by intestinal epithelial cells in vitro and in vivo, and includes the use of cutting-edge technologies such as in vivo phosphoproteomics, and single-cell manipulation during bacterial infection. He also offers a very popular upper-division course in pathogenic bacteriology, and actively mentors undergraduate and graduate students, and post-doctoral fellows at the UA. Keywords: Pathogenic E. coli, Clostridium difficile, infection, host-pathogen interactions

Donata Vercelli, MD, is a Professor of Cellular and Molecular Medicine, the Associate Director of the Arizona Respiratory Center and the Director of the Arizona Center for the Biology of Complex Diseases. Her research work is at the cutting edge of the immunology and genetics of complex lung diseases. Her laboratory spans both human and animal models. After characterizing cellular and molecular events critical for the regulation of human IgE synthesis, she became interested in the mechanisms through which natural genetic variants modify susceptibility to complex diseases, particularly allergy and asthma. To this purpose, she developed innovative, unique mouse models in which distinct human haplotypes of asthma- and allergy-associated genes are carried by BAC transgenic mice and can be directly compared for their regulatory properties in vivo. The unexpected, essential mechanisms underpinning the involvement of Th2 cytokines in allergy and asthma revealed by this mouse model have been fully validated in human populations. Dr. Vercelli's work on the epigenetic regulation of Th2 cytokine expression in human neonatal T cells revealed novel facets of early life regulatory events and her continued interest in epigenetics has led to the first demonstration that neonatal DNA methylation signatures in innate immunoregulatory pathways predict asthma during childhood. Most recently, Dr. Vercelli has devised a highly innovative approach that combines epidemiologic, biochemical and mouse model studies to dissect the mechanisms underlying the asthma-protective and asthma-promoting effects of two distinct US farming environments (Amish and Hutterite). Such studies are likely to critically advance our knowledge about fundamental mechanisms of asthma pathogenesis.

Vercelli Lab Website

Dr. Schlenke's research program uses fruit flies in the genus Drosophila to understand the evolutionary genetics of host-parasite interactions. For example, his lab has developed several species of parasitic wasps, which are readily observed infecting Drosophila in nature and can be very specialized to particular host species, as model parasites. These wasps lay single eggs in Drosophila larvae and, once hatched, consume flies from the inside out. Flies mount cellular and behavioral defense responses against wasps, but wasps have adaptations for finding host fly larvae, suppressing host cellular immunity, and manipulating host behavior. The Schlenke lab uses a variety of "omics" tools to understand the molecular genetics of fly cellular immunity and wasp virulence, as well as patterns of host immunity and pathogen virulence coevolution across fly and wasp phylogenies. The Schlenke lab also studies the genetics and neurobiology of behaviors that flies use to avoid being infected by the wasps and to cure themselves once they are infected, including various self-medication behaviors.

My research program lies in one more focused and two broad and interconnected areas of aging research and intervention. a. Infection and immunity with aging. Over the past 15 years my group has systematically investigated alterations with aging of the immune system and its interactions with acute and persistent microbial pathogens. In the process, we have discovered and described multiple and cumulative defects in microbial detection, initial recognition and uptake by the innate immune system, processing, presentation and initiation of the adaptive immune response, generation of effector immunity and of memory responses and homeostasis and long-term regulation of lymphocyte subsets. We have followed up that work with attempts to correct molecular and cellular defects using novel vaccination and thymic rejuvenation models in mice and non-human primates, and by validating the observations from these models in humans, as well as deriving primary data from human subjects on these same topics. . There is no doubt that I will continue this work on both tracks: primary, basic research will be performed in the mouse, human or NHP model, and, depending on suitability, may be also validated in other models. Translation will be performed in human or NHP models, where we will seek to intervene therapeutically to improve outcomes of infection in older adults. The ultimate goal for the next decade of my career and beyond will be to produce palpable improvement in the immune system of older adults so as to increase success of vaccination and resistance to infection. b. Inflammation in aging: causes and consequences. This is a broader interest of mine, that intersects not only with the immune system, but also with microbial colonization, gut barrier function, metabolism, adiposity and energy sensing. Why do older adults exhibit increased signs and markers of systemic inflammation? Is this inflammation multifactorial, or does it lie in an overexcitable immune system, or increased proinflammatory adipose mass or altered microbial colonization and increased permeability of different (mostly mucosal) barriers? Or a combination thereof? Can we conclusively intervene against diseases of aging and, perhaps, normal aging itself, by modulating inflammation? Microbiome sequencing, deliberate colonization with specific microflora, depletion of different immune cell subsets and/or antibiotic and anti-inflammatory treatments as well as metabolic intervention will all be combined to understand and treat these conditions and their impact upon aging. c. Interventions to extend healthspan and longevity. Advances in the biology of aging have now reached the point where it is no longer unrealistic to put the incredible promise of health-prolonging anti-aging intervention to use in humans. One must: (i) understand effects of life extension in model organisms upon healthspan and end organ function; (ii) carefully dissect signaling pathways that lead to the measured outcomes and validate them in higher primates or humans; and (iii) intervene along these pathways to apply life and healthspan extension treatments. We are currently in the process of multidisciplinary collaborative studies to understand end-organ function and quality of life in the course of different mTOR pathway manipulations in adult and aged mice. Drug discovery program will follow to optimize treatments, and translation will be attempted subsequently in primates and humans.

Katrina Miranda, PhD, claims nitric oxide (NO), which is synthesized in the body via enzymatic oxidation of L-arginine, is critical to numerous physiological functions, but also can contribute to the severity of diseases such as cancer or pathophysiological conditions such as stroke. This diversity in the responses to NO biosynthesis is a reflection of the diverse chemistry of NO. For instance, NO can alter the function of enzymes by binding to metal centers. This type of interaction could result in outcomes as disparate as control of blood pressure or death of an invading bacterium. NO can also be readily converted to higher nitrogen oxides such as N2O3 or ONOOH, which have very different chemical and biological properties. The ultimate result will depend upon numerous factors, particularly the location and concentration of NO produced. Therefore, site-specific modulation of NO concentration offers intriguing therapeutic possibilities for an ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These projects are designed to answer questions of potential medical importance through a multi-disciplinary approach, including analytical, synthetic, inorganic and biochemical techniques.The project categories include five major disciplines. First, she will work on the development and utilization of analytical techniques for detection and measurement of NO and other nitrogen oxides as well as the resultant chemistry of these species. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment

Lonnie Lybarger, PhD, is an Associate Professor in the Department of Cellular and Molecular Medicine within the College of Medicine at the University of Arizona. Dr. Lybarger’s research program focuses on the mechanisms that regulate the activation of immune responses. In particular, his group studies a process known as antigen presentation, which is central to many aspects of the immune response against pathogens and tumors. This work includes detailed analyses of the cell biology of antigen presentation, as well as the study of its impact on immune responses. Recently, Dr. Lybarger has begun to study the critical link between antigen presentation and the regulation of metabolic homeostasis, with relevance to conditions such as type II diabetes.Research in the Lybarger lab has been funded by grants from State and National agencies. He has been an author/co-author on ≈35 original research reports, with his major contributions coming in the field of antigen presentation. Many of these reports involve collaborations within the University of Arizona and with colleagues at other institutions. Dr. Lybarger has served as a reviewer for University and National granting agencies, as well as reviewing for many research journals. In addition, Dr. Lybarger has served as a primary research advisor to a number of graduate and undergraduate students, while contributing to the classroom instruction of medical and graduate students.

Dr. Ledford’s current work in the area of pulmonary surfactant immunobiology combines her knowledge of mouse genetics, pulmonary disease models and immune function regulation and focuses on understanding the role of Surfactant Protein-A (SP-A) and how it regulates signaling pathways within various immune cell populations. Specifically, she is interested in how SP-A regulates degranulation, either directly or indirectly, of two important cell types in asthma: mast cells and eosinophils. More recently, Dr. Ledford’s research has focused on understanding how genetic variation within human SP-A2 alters functionality of the protein in relation to eosinophil activities and how this translates to characteristics observed in human asthma.