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.
William W. Andrews, MD Dr. Andrews is a Professor in the UAB Maternal-Fetal Medicine Division, and has been the Director of the Obstetrics and Gynecology Infectious Disease Research Laboratory since its creation in 1990. Dr. Andrews' research interests relate to obstetrical infections and infection-related preterm birth. He is the PI for an investigation of Interconceptional Antibiotics to Prevent Recurrent Preterm Birth that was recently completed and is the protocol chairman of a prospective randomized trial within the NICHD MFM Units Network of antibiotics to prevent preterm birth in women with elevated mid-trimester cervical fibronectin that is in the analysis phase. He is also the PI of Project IV within the UAB Rural Perinatal Emphasis Research Center which is an evaluation of a neonatal sepsis-like syndrome related to in utero maternal cytokine exposure. Most recently he was awarded a contract to perform "A Longitudinal Study of Bacterial Vaginosis". Dr. Andrews is a consultant and co-investigator on numerous other interdisciplinary projects related to genital tract infections, sexually transmitted diseases, and preterm birth, and he is a co-investigator within the International Clinical Epidemiology Network (INCLEN).
William H. Benjamin, Jr, PhD Dr. Benjamin is involved in Streptococcus pneumoniae antibiotic resistance epidemiology and mechanisms as well as trials evaluating responses to S. pneumoniae vaccines. The frequency of resistant strains of the pneumococci has increased dramatically in the last few years, making effective vaccines more important than ever. There are now several polysaccharide or polysaccharide protein conjugate vaccines approved and in widespread use. The clinical trials determining efficacy of these different preparations are large and expensive. The relatively low number of clinically severe infections seen in these trials makes in vitro tests that correlate with protection a very important goal. We have access to a large number of sera from multiple different vaccine trials and are developing improved ELISA and opsonophagocytosis assays which should correlate with clinical efficacy better than tests now used. I am also working on developing molecular tests to identify the capsular type of S. pneumoniae for use in vaccine evaluation. There are 90 serotypes of S. pneumoniae and because the polysaccharide vaccine contains 23 polysaccharides and conjugated vaccines have only 7 to 11 serotypes, it is important to determine the capsule types of strains that cause disease but more importantly those being carried by the vaccinated and control populations in studies. The current method of manual agglutination using sets of 90 antisera is extremely labor intensive which puts definite constraints on the number of isolates that can be typed from any individual as well as limiting the size of studies that are feasible. If a PCR based test for the various capsule genes can be used to accurately and efficiently serotype isolates or even the total types present in nasal washings. Recent research has shown that serotypes not in the vaccines used in the trials are replacing the vaccine serotypes, though it is not known if these classically less virulent serotypes will have increased virulence.
Suresh B. Boppana, MD Dr. Boppana’s laboratory is studying the pathogenesis of congenital cytomegalovirus (CMV) infections. Congenital CMV infection is the most frequent congenital infection and a leading cause of brain damage and sensorineural hearing loss in children. The focus of the work in our laboratory include: 1. Understanding the intrauterine transmission of CMV in women who were CMV seropositive before pregnancy. We recently showed that acquisition of a new CMV strain is associated with intrauterine transmission and damaging congenital infection in immune mothers. Our ongoing studies will attempt to define the role of maternal reinfection, maternal strain-specific immune responses and other factors in transplacental transmission and damaging congenital infections in infants born to immune mothers; 2. Definition of the mechanisms of hearing loss, in particular, the development of late onset and/or progressive hearing loss in children with congenital CMV infection. We are investigating the role of virus burden and characterizing the virus specific cellular immune responses in congenitally infected children to better delineate the pathogenesis of hearing loss in children with congenital CMV infection; 3. Understanding the virologic and immunologic characteristics of primary CMV infection.
David E. Briles, PhD We study the interactions of host defenses and bacterial virulence factors in the pathogenesis of bacteria. Our approach is to use both bacterial and animal genetics to identify and study important mechanisms in protection and virulence. We have identified a cell wall protein of pneumococci, PspA, which is important for pneumococcal virulence and which may be useful as a vaccine for very young children. Studies are underway to characterize the protection-eliciting portion of PspAs from different childhood strains of pneumococci, and to assemble these into an effective human vaccine with other pneumococcal proteins. We are studying the mode of action of several pneumococcal virulence factors including pneumolysin, PspC, PsaA, and autolysin, and are investigating the possibility of developing a pneumococcal vaccine that would prevent pneumococcal carriage. In other studies, we are investigating the effects of specific immunity and inflammation induced host immunity on the in vivo killing and growth rates of Streptococcus pneumoniae.
William J. Britt, MD Our laboratory has focused its efforts on two important aspects of the biology of herpesviruses; virus assembly and the pathogenesis of human cytomegalovirus (CMV) infections. We have developed several in-vitro assay systems that permit the identification and characterization of critical protein interactions that take place during virus assembly. Using BAC derived infectious clones, we have utilized virus genetics to understand the role of different viral proteins in the assembly of an infectious particle. Our results indicate that interactions between viral tegument and envelope proteins are essential for infectious particle assembly and that inhibition of these interactions can limit envelopment and therefore, virus assembly. A second major focus of our laboratory is the development of a small animal model of CNS disease associated with cytomegalovirus infections. We have exploited a finding that newborn mice infected with murine CMV develop CNS infection that leads to maldevelopment of the CNS, including abnormalities in cellular migration. This system is now being characterized both in terms of host responses and viral genes that are required for this disease phenotype.
Kevin S. Harrod, PhD Dr. Harrod’s research goals are grounded in the use of emerging or high throughput technologies to elucidate system-wide knowledge of host-pathogen interactions in respiratory infection. He has a primary focus in the molecular mechanisms underlying pathogenesis, immunity and host defense to respiratory viruses such as influenza, paramyxoviruses and SARS-CoV, and a long-standing interest in community-acquired bacterial infections of the lung including sepsis.
Hui Hu, PhD Utilizing a broad variety of techniques including cellular immunology, molecular biology, biochemistry, gene-targeting (knockout and knockin), functional genomics and in vivo animal models, the Hu laboratory is interested in identifying novel regulatory genes and transcriptional networks that play critical roles in regulating the adaptive immunity. One of the research projects in the Hu laboratory is to study T follicular helper (Tfh) cells and germinal center (GC) responses (Nat. Immunol. 2014). The complex regulation that determines the initial development of Tfh cells, their developmental progression in germinal centers, and their fates after an immune response dissolves, is still not fully understood. The Hu laboratory is interested in identifying novel pathways underlying the differentiation of Tfh cells in humoral responses and designing new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders. The Hu laboratory is also working to find ways to activate T cells under immunosuppressive circumstances. The Hu laboratory has demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state. If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge (Nat. Immunol. 2011). The Hu laboratory is interested in identifying regulatory genes and pathways that actively restrain T cell activation, and defining the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.
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.
John F. Kearney, PhD The overall research plans of his laboratory are aimed at discovering fundamental cellular and molecular mechanisms involved in the development the development of T and B lymphocytes. The development and establishment of the B cell repertoire is the net result of both genetic and environmental forces. These are dynamic processes beginning with the earliest expression of immunoglobulins in fetal life and continuing throughout life. Immunoglobulin transgenic and knockout mice models are used to define the antigens involved in the selection process, to determine the phenotypes of B cells at different states of differentiation and selection, and to seek out the fetal and adult anatomical sites where positive and negative selection of B cells occurs. The impact of terminal deoxynucleotidyl transferase activity (Tdt) expression on the diversity of immunoglobulin CDR3 regions and the subsequent effects on fetal perinatal and adult B cells, is being addressed by the use of transgenic mice in which N region additions have been introduced during stages of B cell development when such additions are normally absent or minimal. The molecular and cellular differences between B cell subsets are compared in studies on precursor/progeny relationships using newly developed monoclonal antibodies as cellular markers, and the use of a variety of transgenic and knockout mice.
Based on his knowledge of the mechanisms of immune responses in mice he is also involved in understanding the mechanisms of B. anthracis spore-host interactions to facilitate the subsequent design and development of preventive, interventive and diagnostic procedures of the causative organism of Anthrax. He is using mouse models to define protective immune mechanisms against spore entry and to define mechanisms of immunopathology and immune evasion of the ungerminated spores in the host. Mechanisms of spore attachment, routes of spore entry into the body and spore -host interactions within the immune system are being studied. Emphasis is placed on understanding mechanisms of spore entry and immunoregulation in the skin, gastrointestinal tract, respiratory system and also spore passage in the blood. The experiments outlined in this area of research will aid in our understanding of the role that fetal and neonatal B cells play in establishment and maintenance of the normal immune system and will provide insight into their roles in autoimmune diseases, B cell neoplasia, immunodeficiency diseases and the development of more efficient vaccines against anthrax and other disease producing organisms.
Beatrz Leon, PhD The major research interests of the laboratory include studying the in vivo regulation of T cell responses by dendritic cells (DC), including the control of effector CD4 and CD8 T cells responses and the modulation of memory T cells. One of the lab’s major projects is to characterize the roles that DC subpopulations play in the induction of T Helper 2 (Th2) responses to common allergens that trigger allergic asthma. Infants are three to four times more prone to allergies than adults. Therefore, emphasis is placed on understanding the different molecular mechanisms involved in activation of T cells by infant and adult DC. In a second project, the lab evaluates the mechanisms determining the commitment and plasticity of memory follicular helper CD4 T cells (Tfh) cells and their role in allergy. Finally, the lab also studies how maternal alterations of bacterial microbiota affects asthma risk in offspring.
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.
Sadis Matalon, PhD Dr. Matalon’s research interests focus on the role of free radicals as protective agents and as mediators of tissue injury, specifically in the context of the alveolar epithelium. Currently, two approaches are being pursued. The first is an investigation of the role of reactive oxygen-nitrogen intermediates in the killing of Mycoplasma pneumoniae. These mycoplasmas account for 20 to 30 percent of all pneumonias in humans, and exacerbate the pathophysiology of asthma, chronic obstructive disease and other pulmonary diseases. Man is the only host of M. pneumoniae, but M. pulmonis infection in mice provides an excellent animal model that reproduces the essential features of human disease. Moreover, C3H/He mice are susceptible but C57BL/6 mice are resistant. Presently, the basic mechanisms by which some hosts, but not others, kill mycoplasmas in vivo have not been elucidated. Dr. Matalon and colleagues have hypothesizes that in the early stages of infection, mycoplasmas are killed by reactive oxygen-nitrogen intermediates (ROS) produced by activated alveolar macrophages (AM). Surfactant protein A (SP-A) is essential and necessary or this killing to occur by (i) upregulating production of nitric oxide by activated AM, and (ii) stimulating phagocytosis of mycoplasmas by AM. Furthermore, injury to SP-A by reactive oxygen-nitrogen species abrogates its host-defense functions. This hypothesis is being tested in vitro, using AM isolated from the lungs of these mice, and in vivo using congenic germ-free knock-out mice. The second series of studies involves analysis of hyperoxic injury. Active sodium (Na+) transport across the adult alveolar epithelium plays an important role in the maintenance of lung fluid balance, especially after sublethal hyperoxic injury to the blood-gas barrier, when the effectiveness of the passive Starling forces is diminished. Presently, the mechanisms by which Na+ ions enter the apical membranes of normal and oxygen-injured alveolar epithelial cells, have not been elucidated. Based on preliminary data, Dr. Matalon and colleagues hypothesize that alveolar type II cells (ATII) contain Na+ channels with low affinity to amiloride and that the properties and spatial distribution of these channels may be altered by exposure to sublethal hyperoxia. Since sodium channels conduct at rates far exceeding that of any other transporter, and their activities may be upregulated by a number of agents, they may form a major pathway for the entry of Na+ ions into alveolar epithelial cells.
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. Mountz, MD, PhD A hallmark of autoimmune disease is the development of autoantibodies that can cause disease. My laboratory has identified that the second recombinant inbred strain of B6 x DBA/2 (BXD2) spontaneously produces very high levels of pathogenic autoantibodies. Single antibodies produced by hybridomas from spleens of these mice transfer arthritis or glomerulonephritis in normal mice. By 3 months of age, the spleens of BXD2 mice are greatly enlarged and are packed with numerous large, spontaneous germinal centers (GCs). This GC development is promoted by high levels of Th17 and IL-17 in these mice. IL-17 signals through the IL-17a receptor in B cells resulting in increased classical NF-κB pathway activation. This activates several genes, including regulators of G-protein signaling (RGS) 13 and 16. Upregulation of RGS genes impairs signaling through CXCR4/CXCL12 and CXCR5/CXCL13 to arrest migration and movement of T cells and B cells. This enables prolonged and stable interaction of B cells and CD4 T cells. Key ongoing questions in my laboratory include what is the mechanism for increased Th17 development. IL-6 is highly produced by B cells, macrophages and plasmacytoid dendritic cells (PDCs). TGF-β, however, is not greatly increased. What are the factors, in combination with IL-6, that promote high Th17 development in BXD2 mice? How does Th17 signal through B cells? Our recent evidence indicates that IL-17 signaling requires both TRAF6 and ACT1, which has been identified in IL-17 signaling pathways. Current ongoing work is to determine the mechanism of increased NF-κB signaling in response to IL-17 in B cells. Also using RGS13 KO and RGS16 KO mice, we wish to determine which of these RGS proteins is highly essential for development of spontaneous autoreactive GCs. We also wish to identify the most promising points for interruption of IL-17 signaling that upregulates RGS expression in B cells. Other studies include detailed analysis of the effect of IL-17 on B cell chemotaxis in response to CXCL12 and CXCL13. These include in vitro chemotactic chamber analysis, and live imaging analysis using confocal microscopy.
A second area of interest is the role of DR5 apoptosis in arthritis and autoimmune Disease. TRAIL-DR5 apoptosis signaling is very similar to FAS apoptosis signaling involving mitochondrial amplification loop and Bcl-2 family members, as well as direct induction of apoptosis through caspase activation resulting in terminal caspases 3, 5, and 7 activation. The TRAIL-DR5 apoptosis signaling pathway, like Fas, is inhibited by FLIP-L and XIAP (inhibitors of apoptosis proteins). DR5 is upregulated on synovial fibroblasts of patients with rheumatoid arthritis and in Collagen-II mouse model of arthritis. To determine mechanisms of DR5 apoptosis in vivo, we have produced a human-mouse (hu/mo) chimeric DR5 transgenic mouse. This mouse transgene is driven by the 3 kB mouse DR5 promoter and is regulated by a Floxed-STOP between the promoter and the hu/mo chimeric DR5 transgene. Thus, expression of hu/mo DR5 chimeric transgene can be targeted to synovial fibroblasts, B cells, T cells, or macrophages. In collaboration with Dr. Tong Zhou, we are analyzing the ability of a novel anti-human DR5 antibody (TRA8) to regulate arthritis and immune responses in these chimeric DR5 transgenic mice.
My laboratory has longstanding interest in age-related immune senescence. We were one of the first investigators to propose that T cell senescence is due to decreased, rather than increased, apoptosis. This was directly demonstrated using a CD2-Fas Tg mouse that resulted in increased expression of Fas throughout the lifespan of the mouse. This resulted in decreased T cell senescence. Our recent interest in T cell senescence is being carried out in a study of nonagenarians in collaboration with Dr. Michal Jazwinski (Tulane University) and Dr. Donald Scott (University of Pittsburgh). Nonagenarians are protected from immune senescence by several factors including increased levels of certain hormones, such as leptin and Insulin like growth factor binding protein 3 (IGFBP3). Our ongoing studies are further characterizing methods to prevent immunosenescence with aging. This is relevant to preservation of immune responses tat may help prevent development of cancer, and provide adequate protection against viruses.
Moon Nahm, MDPneumococci are Gram-positive bacteria that are responsible for several important diseases such as pneumonia, meningitis, sepsis and ear infections. The most important virulence factor of pneumococci is their polysaccharide (PS) capsule. The main host defense against pneumococci is the production of anti-capsule antibodies. To study host-bacterial pathogen interactions and to improve pneumococcal vaccines, my laboratory studies the pneumococci's capsules and the hosts' anti-capsule antibodies. Pneumococci can evade host antibodies since they can produce many serologically distinct PS capsules (more than 90 serotypes). Out studies of diversity in pneumococcal PS capsules led us to discover new, previously unrecognized serotypes. One new serotype is 6C, which had previously been misclassified as serotype 6A. We have shown that 6C is chemically and genetically distinct from 6A, that its infection is not prevented by the currently available vaccine, and that its prevalence has been increasing worldwide. Based on our work on serotype 6C, we predicted and have discovered a new pneumococcal serotype 6D. These findings have had a great impact on pneumococcal vaccine developments and evaluations. Recent studies led us discover another new serotype, 11E. Serotype 11E is almost identical to serotype 11A, but 11E has inactive wcjE whereas 11A has a functional wcjE, a gene responsible for acetylating capsular PS. Our epidemiologic survey showed that 11E is rare among the isolates from the nasopharynx, but common among isolates from the blood. All isolates of serotype 11E are genetically distinct (i.e., have distinct wcjE inactivation patterns) and may have been derived from serotype 11A independently in each individual. These findings supports a hypothesis that innate immune factors present in the nasopharynx favors serotype 11A but innate immune factors in the blood favors serotype 11E. We are currently investigating this hypothesis. Our studies have also led us to develop various bio-technologies such as multiplexed assays for antibody function (MOPA) and automated serotyping of pneumococci (Multibead Assay). We are also investigating a new way to diagnose pneumococcal pneumonia based on the biochemical changes observed during pneumonia infections. These bio-technologies are of fundamental importance in developing pneumococcal vaccines and are widely used. Because of our development of these technologies and our expertise with pneumococcal antibodies, our laboratory is serving as the Reference Laboratory for both the NIH and the World Health Organization.
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.
Alexander J. Szalai, PhD Dr. Szalai is collaborating extensively with several members of the faculty in a series of integrated studies of C-reactive protein (CRP), complement, and Fc receptors; different components of the innate immune system. These studies currently include analysis of the mechanisms that operate to affect the host defense function of CRP and complement against pathogens (Streptococcus pneumoniae), the role of CRP and complement in autoimmune diseases (SLE, MS), and the role of CRP in cardiovascular diseases (atherosclerosis, restenosis, heart transplant rejection). CRP is a 110-kDa protein made up of five identical subunits. It binds phosphocholine, activates the classical pathway of complement, and is recognized by FcgRI and FcgRII. CRP specifically recognizes pathogenic microorganisms and damaged cells of the host and initiates their elimination. Dr. Szalai has used CRP-transgenic mice (CRPtg) to dissect the mechanisms operating to affect the innate host defense function of CRP. His investigations established that CRP-dependent protection against pathogens, such as Streptococcus pneumoniae and Salmonella typhimurium, is effected mainly by clearance of pathogens during the early post-infection period. Complement is not required for this function. In parallel studies of the mode of induction of the CRP gene in vivo, testosterone was found to control basal expression; whereas complement protein 5a, acting together with pro-inflammatory cytokines, is critical for acute-phase induction of CRP. Current studies include determination of the contribution of Fc receptors to CRP-mediated protection using CRPtg/FcgR-deficient mice, and analysis of the effects of CRP expression on serum antibody responses. In addition, Dr. Szalai actively participates in several clinical studies, and is now investigating allelic differences in the expression of CRP in healthy versus diseased individuals. CRP is routinely used as a plasma marker of inflammation in inflammatory diseases. As family studies have demonstrated genetic influences in SLE, with linkage to several regions on human chromosome 1 and the CRP gene is located within one candidate linkage region, genetic differences in this gene could be related to the lupus diathesis. Dr. Szalai has evaluatied the association of a (GT) repeat polymorphism in the intron of the CRP gene with plasma levels of CRP and the clinical phenotype of SLE in collaboration with Dr. Robert P. Kimberly. Finally, Dr. Szalai is using two different mouse models to determine the role of CRP in the development of autoimmune disease. CRP-transgenic (NZB X NZW)F1 mice (BW) exhibited delayed onset of SLE and their lifespan was extended significantly compared to that of non-transgenic BW mice. However, the anti-double stranded DNA autoimmune response occurred earlier and was enhanced in the CRP-transgenic mice, and there was deposition of CRP in nephritic kidneys. Current studies seek to determine the mechanism for the CRP-protective effect. The onset of experimental allergic encephalomyelitis (EAE, a model for MS) is delayed in female CRP-transgenic mice compared to wild-type mice. This protective effect is causally related to the transient upregulation of the CRP transgene observed during the early stages of disease development. In collaboration with Dr. Scott Barnum, Dr. Szalai is now testing the hypothesis that the duration of CRP-mediated protection against EAE will be extended in CRP-transgenic mice by prolonging and/or increasing expression of CRP, which may be achieved through the influence of sex hormones that regulate CRP expression. Mutant mice that are not able to fully activate the complement system due to engineered deficiency in C3 or factor B, exhibit reduced clinical symptoms of EAE, cellular infiltration, and demyelination. When complement-deficient mice hybridized with CRP-transgenic mice were tested, a delay in both the CRP-mediated delay in onset of EAE and the complement deficiency-mediated reduction of disease were observed. These data show that the CRP-protective effect in EAE is realized whether or not a fully functional complement system is present, suggesting that CRP is mediating its protection through other mechanisms. Dr. Szalai's most recent work, performed in collaboration with groups at Harvard, UCSD, Baylor, and UAB, showed that CRPtg mice exhibit ia pro-thrombotic/pro-atherosclerotic phenotype, but experience reduced neointimal growth following vascular injury.
Charles L. Turnbough, Jr. PhD Currently, there are three major research projects in Dr. Turnbough's laboratory. The first project is to identify and determine the function of the components of the exosporium of spores of Bacillus anthracis, the causative agent of anthrax. The exosporium, the outermost layer of the spore, is composed of polysaccharides, lipids, and ~20 different proteins. It is the primary site for spore interactions with the environment and host defenses and presumably plays major roles in spore survival and pathogenesis. The ultimate goal of this project is to identify macromolecular factors on the surface of the B. anthracis spore that are potential targets for new vaccines and drug intervention for the prevention and treatment of anthrax. The second project is to discover ligands that can be used to capture and detect B. anthracis spores. The group is focusing on two types of ligands – short peptides and monoclonal antibodies (mAbs). Using phage displayed peptide libraries, they have identified ~7 amino acid-long peptides that bind tightly and species-specifically to B. anthracis spores. They are also characterizing the spore receptors/antigens to which the peptide ligands/mAbs bind. The third project focuses on mechanisms of gene regulation in Escherichia coli that involve reiterative transcription and/or transcriptional start site switching. Reiterative transcription is the repetitive addition of a nucleotide to the 3’ end of a nascent transcript due to slippage between the transcript and DNA template. Start site switching is the selection of alternative start sites at a single promoter, which results in the synthesis of transcripts with different potentials for translation. Previous studies in the lab have described control mechanisms in which reiterative transcription during initiation and/or start site switching regulates the expression of several operons involved in pyrimidine biosynthesis and salvage. Recently, Dr. Turnbough's laboratory discovered additional operons that appear to use reiterative transcription and/or start site switching to regulate their expression by mechanisms unlike those previously described. These new mechanisms are presently being elucidated. In addition, studies are in progress to define the mechanisms of reiterative transcription and start site switching and the factors that modulate the extent of these reactions.
Janet L. Yother, PhD Dr. Yother's laboratory is interested in the genetic basis of pathogenesis of Streptococcus pneumoniae, an important cause of otitis media, meningitis, and pneumonia. The polysaccharide capsule of S. pneumoniae is a major virulence factor of the organism. However, the role of capsular serotype per se and of non-capsular factors is less clear. In one area of study the group is examining the specific role that capsular type plays in virulence. Using molecular genetic techniques, they have localized and characterized genes required for capsule expression and have constructed isogenic strains differing only in capsular type. These strains are being used in animal studies to determine whether specific virulence properties are affected by capsular type. These studies will allow the group to determine the genetic basis of capsule expression with respect to identity, function, regulation, and evolution.
A second area of study involves pneumococcal surface protein A (PspA), a protection-eliciting molecule that is also a virulence factor of S. pneumoniae. DNA sequence analysis indicated that PspA has four distinct domains. Dr. Yother's studies are directed towards determining the functions of these domains in virulence, variability, and anchoring of the protein to the S. pneumoniae surface. An unusual mechanism of anchoring by PspA has led to studies involving protein secretion and novel systems for expressing and easily purifying heterologous antigens from S. pneumoniae.
Allan J. Zajac, PhD Research in Dr. Zajac's laboratory is focused upon understanding how the immune response combats viral infections. They are particularly interested in elucidating how antiviral T cell responses are initiated, how they successfully resolve many viral infections, and why these responses are sometimes ineffective, thus promoting the establishment of persistent infections. One of the best experimental systems for analyzing cell-mediated immune responses is lymphocytic choriomenigitis virus (LCMV) infection of mice. Studies on the immune response to this virus have been extremely informative, providing the first evidence of cytotoxic T cell activity during viral infections and shaping our understanding of such fundamental concepts as MHC restriction and immunological memory. The laboratory has used this system to analyze CD4 and CD8 T cell responses during the course of acute, protracted and chronic infections. Many infections, such as acute LCMV infection, elicit massive expansion of virus-specific CD8 T cells which play a principle role in eliminating the virus. As the infection is controlled, the immune response becomes downregulated, and a stable pool of virus-specific memory cells emerge which confer immunity to viral re-exposure. During protracted or chronic infections a different pattern of virus-specific T cell responses develops as the host fails to control the infection. Under these conditions, virus-specific CD8 T cells are initially induced, but either become deleted or lose effector activities. Virus infections also induce CD4 T cell responses which are critical for the successful resolution of many infections. The group has documented that CD4 T cells drive the functional maturation of CD8 T cell responses in acutely infected hosts and sustain the effector functions of these cells during chronic viral infections. Protracted and chronic viral infections are often associated with weak CD4 T cell responses which consequently fail to support robust antiviral CD8 T cell activities. Dr. Zajac's current research is focused upon determining how to reverse this trend and improve cell-mediated immunity to persistent viral infections. Taken together, findings have broad implications for development of vaccinations and therapeutic strategies to control acute and chronic viral infections as well as malignancies