The investigators in this program are Dr. Allan Yates, Dr. James Waldman, Dr. Joanne Trgovcich and Dr. Vijay Pancholi. The individual areas of expertise include: markers of glioblastoma tumor progression and ganglioside biology (Yates and Saqr laboratory); autoimmune vascular injury, antiviral/immunosuppressive drug development for treatment of viral diseases in transplant patients, and environmental toxicology (Waldman laboratory); herpes simplex type 1 and human cytomegalovirus biology and viral immune evasion mechanisms (Trgovcich laboratory); and pathogenesis of diseases caused by group A streptococcus (Pancholi laboratory). Novel Anti-viral componds: Dr. Waldman has active research projects in progress in the areas of viral pathogenesis, antiviral drug discovery, and environmental toxicology. Dr. Waldman discovered several years ago that the anti-inflammatory, immunosuppressive agent leflunomide (currently in clinical trials in organ transplant recipients) possesses potent antiviral activity against cytomegalovirus (CMV) and herpes simplex virus, both of which are sources of potentially serious complications in immunosuppressed populations. This discovery has led to successful leflunomide treatment of transplant recipients suffering CMV disease. Importantly, since the antiviral mechanisms of this agent are very different than those of traditional anti-CMV drugs, all of which inhibit viral DNA synthesis, leflunomide has been shown to be effective in patients non-responsive to the traditional drugs. More recently, Dr. Waldman’s team has demonstrated leflunomide to also be effective against polyomavirus strain BK (BKV), another source of serious complications in renal transplant recipients, and against respiratory syncytial virus, a common cause of serious respiratory disease in infants, immunosuppressed individuals and the elderly. As a consequence, leflunomide has been successfully used to reduce viral load and improve kidney function in renal transplant recipients suffering BKV nephropathy. In collaboration with Dr. Prabir Dutta, Department of Chemistry, Dr. Waldman’s group is also investigating oxidative stress and inflammatory responses induced by airborne nano-particulates. A major goal of these studies is to correlate chemical reactivity of the particulates with their biological activity and, thus, to identify specific particulate physicochemical characteristics which predict biological responses. Viral Pathogenesis: The primary research effort in Dr. Trgovcich’s laboratory is the discovery and characterization of strategies by which herpes simplex type 1 (HSV-1) and human cytomegalovirus (HCMV) evade or modulate host immune responses. Towards this end, we are investigating the biology of these ancient viruses at a molecular/genetic level, including the application of transcriptomic and genomic methods to identifying novel viral genes or gene functions which may influence host immune responses. In the course of these studies, we made the unexpected discovery that virally-derived antisense and noncoding transcripts accumulate to very high levels during lytic infection. This work was published in the Journal of Virology. They are interested in pursuing studies to investigate whether these antisense and noncoding transcripts function in epigenetic gene regulatory processes. One of the original goals of these studies was to use this library to identify genes which disrupt cellular antiviral responses mediated by interferons. After screening only the first 80 of the 604 cDNA clones isolated, they identified two candidate viral genes whose products function in disrupting interferon signaling. They are currently preparing a manuscript detailing the activity of the first of these candidates. A second major area of research in their laboratory is collaboration with Dr. Van Brocklyn and Dr. Waldman to investigate if and how sphingolipid signaling pathways are impacted by virus infection. This is an essentially unexplored are of viral pathogenesis research. Because sphingolipid signaling impacts several fundamental physiological processes, they sought to determine if and how this system was altered upon virus infection with human cytomegalovirus. Thus far, they have discovered that host cell sphingolipids are dynamically regulated upon infection with HCMV in a manner that promotes virus gene expression. These findings warrant further studies to ascertain if and how virus infection impacts the activities of sphingolipids via receptor-regulated cellular processes such as cell survival, proliferation, motility. Also, considering the important role of sphingolipids in regulation of lymphocyte trafficking and immune responses, further studies to investigate how HCMV and other viruses interface with this signaling system may ultimately shed light on virus replication, spread and pathogenesis. To our knowledge, this is the first report of regulation of sphingolipid metabolism upon infection by a member of the herpesviridae family. This work is in revision for publication in the Journal of Virology. Bacterial Pathogenesis: The major emphasis of Dr. Pancholi’s laboratory is to understand the pathogenesis of diseases caused by group A streptococcus (GAS), Staphylococcus aureus (Staph) and Enterococcus faecalis/faecium (enterococci). They are also investigating the mechanisms of multidrug-resistance observed in hospital- and community-acquired S. aureus and Enterococcus faecalis and E. faecium. Using several cell biology, molecular and biochemical approaches, they understand the mechanisms of cell-cell interactions between microbes and host cells. They then investigate the impact of these interactions both in the host and pathogens by global genomic and proteomic approaches utilizing microgene array and mass spectrometric technologies. Based on these findings, they have identified newer and underappreciated factors which play important roles in the pathogenesis of the diseases. Using these approaches, they have identified five anchorless surface metabolic enzymes in GAS and novel membrane bound protein kinases and co-transcribing phosphatases in GAS, Staph, and enterococci. The anchorless surface proteins play an important role in bacterial adherence and invasion and host cell apoptosis. The kinase/phosphatase enzymes of these organisms play an important regulatory role in bacterial metabolism, cell division, virulence and even drug resistance. Dr. Pancholi’s lab’s present and future approach will lead to understand how bacterial eukaryotic-type serine/threonine kinase exploits host machinery for bacterial survival and progression of the disease. While they further understand the role of these proteins in intracellular signaling events in bacteria and host and hence in the disease process in general, the ongoing investigations on these proteins so far lead us to believe that these factors may serve as targets to develop rational chemotherapeutic and/or immunotherapeutic interventions to effectively counteract GAS, MRSA and enterococcal diseases.