Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.
Noel K. Childers, DDS, PhD Dr. Childer's current studies involve investigations aimed at identifying safe and effective mucosal immunization delivery systems. Specifically, studies examine the characteristics of liposomes that are important in potentiating immune responses to orally or nasally administered S. mutans antigens. This involves in vitro studies of the physical characteristics of liposomal antigen preparations as well as in vivo studies into the uptake and processing of liposome preparations in rats. Following animals studies of the efficacy of liposomal S. mutans antigen vaccines, studies have been initiated for human FDA Phase I clinical trials studying the safety and immunogenicity of liposomal oral and nasal immunization. The overall goal of these studies are to identify a safe and effective oral immunization strategy which is protective against dental caries.
Clinical research interests also include studies to determine risk factors for oral complications in children with cancer and HIV infection. These studies have assessed various clinical and immunological factors involved in the development of oral lesions in medically compromised children. The goal of this research is to develop and test protocols that will prevent the occurrence or severity of oral complications in children identified to be at risk. Additionally, research efforts have involved assessment of the prevalence of dental disease in children as related to access to care. Related studies have assessed the effectiveness of dental sealants in prevention of dental caries using Medicaid claims as well as Jefferson County Department of Public Health records.
James F. Collawn, PhD Dr. Collawn's laboratory studies receptor-mediated endocytosis (RME) and protein trafficking. The first area of focus is to examine the polarized trafficking of two integral membrane proteins in epithelial cells, the transferrin receptor (TR) and the cystic fibrosis transmembrane conductance regulator (CFTR). TR is expressed in nearly all mammalian cells and its itinerary is well characterized by us and others. CFTR is a cAMP activated chloride channel and its transit through the secretory and endocytic pathways is just beginning to be understood. Cystic fibrosis (CF), the most common genetic disorder in the Caucasian population, results from defective processing or function of the CFTR protein. Therapeutic approaches have focused on increasing the amount or improving the function of defective CFTR at the apical membrane. However, until the exact physiological functions and trafficking pathways of wild-type CFTR have been characterized, such treatments remain only empirical. Using biochemical and physiological approaches, Dr. Collawn's group is studying the cellular mechanisms that regulate wild-type CFTR biogenesis, endocytosis, recycling and function. They are also comparing the above features of the wild type protein to naturally-occurring CFTR mutants in order to understand the metabolic and functional defects in these proteins that result in a certain disease phenotype. The group's second area of research is to develop methods that will establish safe and effective strategies for immunization or for induction of immunologic tolerance. Using phage display analysis, Dr. Collawn's lab has identified peptides that bind to cell surface receptors on dendritic and B cells. They are screening for specific receptors that undergo RME in order to develop methodologies for enhancing antigen uptake and processing by antigen-presenting cells in vitro. Using a well-defined transgenic animal model, they are testing the effectiveness of different peptide sequences identified by phage display to promote antigen uptake and presentation and are using this methodology to study how this might be used to either enhance or suppress helper T cell responses in vivo. These studies employ both cell biological and immunological techniques to understand how helper T cell responses are regulated in vitro and in vivo.
Jessy Deshane, PhD Dr. Deshane is committed to an academic career combining basic and translational research with an emphasis on inflammatory diseases of the airway. The focus of Dr. Deshane's research program is to enhance our understanding of the role of myeloid-derived regulatory cells in chronic airway inflammatory diseases. Asthma is a chronic inflammatory disease of the airways in which innate and adaptive immune cells participate as drivers of the inflammatory response. Free radical species have long been implicated as critical mediators of the asthmatic inflammatory process. Dr. Deshane's studies in a mouse model of allergic airway inflammation have established that subsets of free radical-producing myeloid-derived regulatory cells (MDRC) are master regulators of airway inflammation. They are potent modulators of both T cell responses and airway hyper-responsiveness. Dr. Deshane has identified human MDRC with similar function in bronchoalveolar lavage of asthmatics. Her current research interests are (1) to explore the free radical and cytokine/chemokine mediated mechanisms underlying the differentiation and function of myeloid derived regulatory cells in the establishment of airway inflammation and resolution of inflammation (2) to investigate MDRC- mediated regulation of the balance of Tregulatory cells and Th17 cells which control the tolerance vs inflammation (3) to understand how environmental pollutants such as tobacco smoke would impact MDRC function and contribute to exacerbation of inflammation in asthmatic smokers. These studies will provide insight into the role of MDRC in tobacco related pathology of the lung.
Charles O. Elson III, MD The central focus of the laboratory is on the regulation of mucosal immune responses, particularly the mucosal immune response to the microbiota, which represent the largest mass of antigen encountered by the immune system. The cellular and molecular mechanisms that maintain mucosal immune homeostasis are being defined. When these mechanisms fail, pathogenic effector T cells are generated that result in colitis. We have cloned a set of immunodominant antigens of the microbiota that stimulate such pathogenic T cells and result in inflammatory bowel disease. Among these cloned antigens, previously unknown bacterial flagellins have emerged as a major cluster. Seroreactivity to these flagellins is found in multiple experimental models of colitis in mice and in half of patients with Crohn's disease. These antigens drive a newly described CD4 T cell effector subset making IL-17 (Th17) which appears to be responsible for disease progression. A T cell receptor transgenic mouse reactive to CBir1 flagellin has been generated and is being used to study the innate and adaptive immune response to these microbiota antigens. A second major effort is in the identification of T reg cells in the intestine that recognize microbial antigens and maintain homeostasis. The mechanisms whereby such cells are induced are being defined and the application of these cells to prevent or treat intestinal inflammation is being tested. Lastly, a microbiota antigen microarray has been constructed which can be used to analyze serologic reactivity to the microbiota in both mouse and human. Sera from various human populations are presently being analyzed.
Kohtaro Fujihashi, DDS, PhD The mucosal immune system is an internet of tissues, cells and biologic mediators which regulate host responses to the environment. Over 80 % of this immune system occurs in the gastrointestinal (GI) tract and the three major manifestations, e.g., mucosal immunity, inflammation and tolerance can be most conveniently studied there. A number of research projects are underway in our group and these NIH-funded studies involve a number of significant collaborations both at UAB as well as with other Universities and Research Institutes. Specifically, individual projects include 1) The Cellular and Molecular Mechanisms for Mucosal Immunity in the Elderly; 2) Molecular and Cellular Mechanisms for Induction and Regulation of Mucosal Tolerance. 3) A Mucosal Internet of gd, ab T Cells and Epithelial Cells for Mucosal Immunity ; and 4) Mucosal Immunity in Murine Models of IBD.
Jannet Katz, DDS, PhD My research program is primarily directed to understand host/microbial interactions with emphasis on the pathogens Porphyromonas gingivalis and Francisella tularensis. P. gingivalis is involved in the development of periodontal disease, a disease that has been linked to cardiovascular disorders, diabetes, rheumatoid arthritis, low weight babies and complications of patients on hemodyalisis. My studies with P. gingivalis or its purified virulence antigens are centered around the innate and T cell host responses, as well as the signaling molecules and transcription factors involved in order to develop therapies or vaccines against infection. In addition, I recently began studies on the effect of P. gingivalis infection on DNA methylation patterns in general and specifically in the obese population. The second pathogen I work with is F. tularensis, the cause of tularemia. Due to the rapid dissemination of F. tularensis by various routes, it’s ability to infect the host through various mucosal surfaces and the high virulence of some of the strains, F. tularensis is considered a bioterrorism agent. My studies with F. tularensis are geared to understand the potential of this bacterium to infect various organs/tissues, the innate and adaptive immune responses induced upon infection in the context of signaling molecules and pathways, and the potential use of rapamycin as an innovative therapy to ameliorate the infectious process by dampening an exacerbated host response.
Robin G. Lorenz, MD, PhD The focus of research in our laboratory is the study of the cellular components of the mucosal immune system and their interactions with the gastrointestinal epithelium, the GI microbiome, and the systemic immune response. Our first area of interest is the cellular immune response to Helicobacter in a mouse model of gastric infection and inflammation. The bacteria Helicobacter pylori is a major pathogen which is linked to acute and chronic gastritis and adenocarcinoma. It is also linked to protection from esophageal cancers and allergic asthma. We are currently investigating the interactions between gastric Helicobacter infection and asthma susceptibility in a mouse model of lung inflammation.
The second area of focus in our laboratory is the role of the intestinal epithelium and innate immune responses in the development of inflammatory bowel disease (IBD). The chronic intestinal inflammation that characterizes IBD is the result of a poorly controlled mucosal immune response to normal intestinal microbiota. The mechanisms that initiate this aberrant response are not well elucidated; however, one possibility is that a change in the intestinal epithelial barrier results in increased systemic exposure to microbial products. The P-glycoprotein (mdr1a-/-) deficient mouse is a unique model of spontaneous colitis that demonstrates an increase in colonic epithelial permeability, as well as a change in the sensitivity of toll-like receptors (TLRs) to bacterial products. Our laboratory focuses on investigating the relationships between the membrane pump- P-glycoprotein, microbial sensors-such as TLRs, and IBD. These studies utilize both in vivo models of IBD, as well as in vitro primary and continuous epithelial cell culture systems. The understanding of the basic mechanisms by which the host maintains intestinal homeostasis and barrier integrity will lay the foundation for future studies on the regulation of the inflammatory response and the design of therapies for human IBD.
The third focus of our laboratory is the influence of mucosal immune factors on the risk of type 1 diabetes development. The incidence of autoimmune Type I Diabetes (T1D) in both human patients and animal models is altered by genetic and environmental factors. These factors include an increased incidence after exposure to high fat diets and hygienic environments. These environmental effects are reproduced in the NOD mouse model of disease, where animals raised in a sterile environment have an increased incidence of disease. In addition to diabetic effects, these environmental exposures have in common the fact that they alter two components of the gastrointestinal (GI) ecosystem, the resident microbiota and the intestinal immune response. Our research focuses on the interrelationship between the GI microbiota, the intestinal immune response, and the risk of T1D development in the NOD mouse model.
Frances E. Lund, PhD The overarching research objective of the Lund laboratory is to identify the key players that suppress or exacerbate mucosal inflammatory responses with the long-term goal of developing therapeutics to treat immunopathology associated with chronic infectious, allergic and autoimmune disease. One of the lab’s major projects is to characterize the roles that cytokine-producing “effector” B cells play in modulating inflammation and T cell-mediated immune responses to pathogens, autoantigens and allergens. In a second project, the lab evaluates how inflammatory signals regulate the balance between the development of the antibody-producing long-lived plasma cells and the memory B cell compartment within lymphoid tissues. The lab also studies how these cells are maintained long-term at inflammatory sites. Finally, the lab examines how oxidative stress induced by reactive oxygen species impacts inflammation, immune responses and cellular metabolism. In particular, the lab is experimentally modulating the NAD metabolome of immune cell in order to alter the responsiveness of these cells to oxidative stress.
Peter Mannon, MD research in inflammatory bowel diseases is heavily translational and focuses on defining immune response variables with important biological plausibility for disease pathogenesis (e.g. excess production of effector cytokines and cognate receptor expression and signaling) that are also suitable candidates for biomarker status of disease activity, can predict response to treatment and serve as novel targets for clinical interventions. Currently my lab is working on exploiting the dysregulation of the IL-13 pathway in ulcerative colitis to define endotypes that predict response to therapy and link more closely to genetic disease susceptibility loci, examining the molecular basis for shared TCR responsiveness to immunodominant antigens in Crohn’s disease, and examing the role of the microbiome in linking inflammatory bowel disease to metabolic disease
Jiri Mestecky, MD, PhD Molecular-cellular interactions involved in the differentiation of B lymphocytes and epithelial cells of the mucosal immune system and the novel approaches for the induction of the humoral immune response in external secretions represent the primary area of interest in our laboratory. Regulation of the expression of immunoglobulin isotypes, with emphasis on IgA and J chain synthesis, are studied in human systems under normal as well as pathologic conditions. The interactions of IgA molecules of various properties (including those found in IgA-containing immune complexes) with lymphoid cells, macrophages, hepatocytes, eosinophils, and epithelial cells are investigated in a variety of human diseases afflicting the gastrointestinal and genitourinary tracts. Development of vaccines against AIDS and sexually transmitted diseases is pursued using novel antigen delivery systems and combination of immunization routes to stimulate mucosal immunity in the genital tract.
Suzanne M. Michalek, PhD Dr. Michalek’s research program centers around two major themes; the mucosal immune system and the development of mucosal vaccines for the induction of protective immunity, and host mechanisms involved in inflammation, with emphasis on those associated with periodontal disease. Studies related to the former theme are investigating the vectors and adjuvants for the development of mucosal vaccines effective in inducing immune responses. These studies are being done in humans and experimental animal models. Current in vivo studies in humans are testing the effectiveness of mucosal vaccines consisting of a recombinant microbial polypeptide from Streptococcus mutans and adjuvants in inducing mucosal and systemic immune responses. Concurrent studies in vitro are investigating the cell surface receptor (including the co-stimulatory molecules and the Toll-like receptors) and signaling pathways involved in adjuvant activity and in the host’s recognition of the microbial virulence factor. These studies should define improved safe ways to elicit protective responses by mucosal-based vaccines. We are also using these approaches for the development of mucosal vaccines against biological threat agents. Other studies in collaboration with Dr. Noel Childers are designed to develop a childhood vaccine against dental caries. Studies are in collaboration with Drs. Jannet Katz and Ping Zhang involve immunologic, molecular biology and cell biology approaches to define microbial components and host factors involved in periodontal disease. In vivo and in vitro models are being used to define virulence factors of the periodontal pathogens, Porphrymonas gingivalis, which are likely involved in microbial adherence and invasion of the epithelial barrier. Other studies are investigating the cellular mechanisms involve in the ability of this gram-negative bacteria or its components such as lipopolysaccharide to mediate inflammatory responses. These studies also are assessing the role of the Toll-like receptors and the co-stimulatory molecules in responses. The cell types and signaling pathways involved in mediating an inflammatory response, as well as bone loss are also being investigated. Finally, studies are being performed in experimental rodent models to define the role of T cells and their cytokines in periodontitis and to develop vaccines effective in protecting against this inflammatory disease. The results of these studies should help in the development of means to treat/prevent inflammatory diseases.
John D. Ruby, DMD, PhD Genotyping Streptococcus mutans using pulsed-field gel electrophoresis and rep-PCR for investigating transmission of this microorganism in children that have severe-early childhood caries. S. mutans genetic diversity and stability within human populations.Glucose chemotaxis in the oral spirochete,Treponema denticola. Characterizing the cellular mechanisms responsible for the recognition of Treponema denticola by the innate immune system. Understanding the symbiotic nature of oral infections caused by the indigenous flora, i.e, dental caries and periodontal diseases.
Lisa M Schwiebert, PhD The major research interests of the laboratory include studying the physiology and pathophysiology of immune responses within the lung. These interests encompass the study of respiratory disorders in order to understand the cellular and molecular mechanisms that underlie airway inflammation. On-going projects examine how surface molecules, such as CFTR and CD40, regulate the airway epithelial expression of pro-inflammatory mediators, including chemokines and adhesion molecules, that initiate and exacerbate leukocyte migration. In addition, we are examining the anti-inflammatory effects of aerobic exercise on asthma-related immune responses. Through increased understanding of the mechanisms that trigger airway inflammation, we hope to develop novel therapeutic agents that combat airway inflammatory diseases such as cystic fibrosis and asthma.
Ruizhong Shen, PhD Early mucosal HIV-1 Infection. Mucosal surfaces play a major role in HIV-1 transmission and pathogenesis. Virtually all human immunodeficiency virus type 1 (HIV-1) infections, excluding those acquired parenterally, are acquired via the mucosal surfaces of the genital or the gastrointestinal tracts. However, the immediate events between exposure to infectious virus and establishment of infection are poorly understood. We seek to define the biological parameters of HIV-1 entry, infection, and dissemination in genital and gut mucosae. Our current focus includes HIV-1 transcytosis across epithelium, identification of first target cells in mucosae, and the selective entry and transfer of macrophage-tropic HIV-1. A better definition of these early steps in mucosal transmission is necessary in order to develop successful HIV-1 vaccines.
Mucosal macrophages in HIV-1 Pathogenesis. Although the mucosa is the largest reservoir of macrophages in the body and mucosal macrophages play an important role in host defense, studies of monocytes/macrophages in HIV-1 infection have focused on blood monocytes and lymph node macrophages, which have been implicated in the establishment, persistence and pathogenesis of HIV-1 infection. However, the striking and well defined phenotypic and functional differences between blood monocytes and mucosal macrophages preclude the simple extrapolation from findings in HIV-1-infected monocytes to HIV-1 infection of mucosal macrophages. We seek to elucidate the roles of mucosal macrophages in the pathogenesis of HIV-1 infection using purified macrophages from human genital and gut mucosal tissues. Current focus includes the mechanisms of down-regulation of HIV-1 infection in intestinal macrophages and the HIV-1 permissiveness of genital and gut macrophages.
Philip D. Smith, MD Dr. Smith's laboratory investigates the gastrointestinal immune responses to infectious agents and inflammatory stimuli. The mucosal cell functions currently being investigated include macrophage anergy, T regulatory and helper cell function, virus transcytosis, and the regulation of inflammation. The cellular and molecular basis for these responses are investigated by probing purified intestinal macrophages, intestinal lymphocytes and epithelial cells with pathogens such as cytomegalovirus, HIV-1 and Helicobacter pylori or their purified or cloned products. The goal of these studies is to elucidate the cascade of events that regulate mucosal immune responses to enteric pathogens and inflammatory stimuli. Understanding these responses is critical for developing novel therapeutic agents and vaccine strategies for mucosal diseases.
Chad Steele, PhD Research in the Steele Laboratory investigates the innate immune response to pathogens of the lung, specifically the fungal organisms Pneumocystis carinii and Aspergillus fumigatus and the bacterium Pseudomonas aeruginosa. In our fungal work, we have published original articles identifying the beta-glucan receptor Dectin-1 as the predominant pattern recognition receptor for alveolar macrophage-mediated recognition and responsiveness to P. carinii (J Exp Med 198:1677-1688; 2003) and A. fumigatus (PLoS Pathogens 1:e42; 2005) and recently published the phenotype of mice deficient in Dectin-1 in response to A. fumigatus (J Immunol 182: 4938-4946; 2009). Current studies are underway to further define the involvement of Dectin-1 in myeloid cell responses to both organisms using Dectin-1 deficient mice. Moreover, the involvement of Dectin-1 in shaping an “innate IL-17” response to A. fumigatus is also a major focus. With respect to P. carinii, we have recently published that deficiency in the myeloid Src-family tyrosine kinases (SFKs) Hck, Fgr and Lyn paradoxically results in better clearance of P. carinii from the lungs as a result of enhanced alveolar macrophage effector function and heightened lung inflammatory responses (Infect Immun 77:1790-1797; 2009). Current studies are focusing on the SFK-mediated mechanism(s) behind the hyper-inflammatory phenotype and whether it extends to augmented adaptive immune responses as well as parameters of alveolar macrophage activation during SFK deficiency. Finally, we have had a long-standing interest in gamma delta T cells and their role in the immune response to lung pathogens (Infect Immun 70:5208-5215; 2002). Currently, we are investigating the mechanism(s) of gamma delta T cell mediated regulation of lung inflammation and injury driven by the Gram-negative bacterium Pseudomonas aeruginosa.