The investigators in this program are Dr. James Waldman, Dr. Vijay Pancholi and Dr. Abhay Satoskar. The individual areas of expertise include: autoimmune vascular injury, antiviral/immunosuppressive drug development for treatment of viral diseases in transplant patients, and environmental toxicology (Waldman laboratory); pathogenesis of diseases caused by group A streptococcus (Pancholi laboratory), and Treatment of leishmaniasis (Satoskar laboratory).
Novel Anti-viral Compounds
Following up on earlier discoveries of the antiviral activity of leflunomide against cytomegalovirus, herpes simplex virus, and polyomavirus BK (BKV), the Waldman lab has continued studies of the antiviral activity of this agent against respiratory syncytial virus (RSV), a source of often severe, life-threatening respiratory disease in infants and young children, immunosuppressed transplant recipients, and the elderly. We have demonstrated that leflunomide treatment reduces viral load by 3 – 4 orders of magnitude in RSV-infected cotton rats, even when treatment is delayed until day 3 post-inoculation and leflunomide is administered in only 2 doses. In addition studies are in progress to define the specific antiviral mechanisms of this agent against RSV and BKV. Importantly, published reports by others continue to accumulate documenting the successful treatment of CMV disease and BKV nephropathy with leflunomide in human transplant recipients.
In collaboration with Dr. Prabir Dutta, Department of Chemistry, we have continued our studies of the inflammatory activity of environmental and manufactured nanoparticulates of varying physical and chemical properties, and have conducted studies of mechanisms of cellular internalization and trafficking of nanoparticulates. We have also demonstrated antibacterial properties of silver nanoparticles immobilized on synthesized zeolite platforms and are exploring potential clinical applications of this discovery. In addition, we are currently beginning studies of the interactions of nanoparticles increasingly being incorporated in processed food with intestinal epithelium.
Finally, based upon our discovery of a relatively consistent pattern of endothelial-reactive autoantibodies in the sera of patients experiencing Susac’s syndrome, a relatively rare neuro-ophthalmic disorder, we are conducting experiments directed toward identification of the protein targets of these antibodies with the goal of developing a definitive diagnostic test for the syndrome.
The major emphasis of Dr. Pancholi’s laboratory is to understand the molecular and cellular bases of gram-positive bacterial pathogenesis especially related to 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. Additional focus is also on exploiting the use of group A streptococcal products in antitumor therapy.
Dr. Pancholi’s group has characterized the functional role of a conserved eukaryotic-type serine/ threonine kinse and phosphatase in Streptococcus pyogenes, Staphylococcus aureus, and Enetrococcus faecalis. Their findings have indicated that although these are contranscribing proteins, they serve as important one-component signaling molecules and regulate a variety of functions including virulence (S. pyogenes and S. aureus), biofilm formation (Enterococcus and Staphylococcus), bacterial cell division and growth. Microarray – based global gene expression profiles of these mutants have revealed that the loss of virulence is due to the down regulation of several virulence-related genes and genes that are responsible for the carbohydrate metabolism and transport. They also observed that deletion of serine/threonine kinase encoding gene results in the loss of innate drug resistance against betalactam antibiotics. Thus these enzymes can serve as important targets for the development of newer antibiotics.
Additionally, Dr. Pancholi’s lab research is also directed to understand the role of anchorless bacterial surface proteins in the pathogenesis of diseases caused by Streptococcus pyogenes, Streptococcus pneumonie and Staphylococcus aureus. These anchorless proteins are a group of selective metabolic enzyme involved in glycolysis. In the absence of a defined cell surface sorting-machinery, their presence on the bacterial surface has remained enigmatic. Their research has now revealed that one of the glycolytic enzymes of S. pyogenes, GAPDH, is exported on the surface to maintain bacterial virulence as by genetically retaining it in the cytoplasm the pathogenic S. pyogenes was completely attenuated. This approach has now been used to attenuate other gram-positive pathogens to develop future live-attenuated vaccine.
Dr. Pancholi’s recent investigations on the biological functions of the recombinant forms of S. pyogenes eukaryotic-type serine/threonine phosphatase and GAPDH have revealed that they cause apoptosis of human pharyngeal carcinoma cells and thus opens new avenues about their potential role in cancer therapy.
Treatment of Leishmaniasis
Leishmaniasis is a major global health problem and a WHO classified neglected tropical disease. Leishmania parasites constitute a number of species which cause a spectrum of cutaneous (CL), mucocutaneous (ML) and visceral diseases (VL) which collectively afflict over 12 million people with approximately 2 million cases occurring annually (www.who.int). Recently, this disease is increasingly seen in military personnel serving in Leishmania endemic countries such as Iraq and Afghanistan, as well as canine population in the US Although the immunological aspects of parasite control are well understood in mouse models of infection, there is no effective vaccine available for leishmaniasis. In addition, drug-resistance is an increasingly important problem hampering effective disease control (www.who.int). Morbidity and mortality associated with different types of Leishmania infections is primarily due to immunopathology that develops during infection.
Dr. Satoskar’s group is interested in understanding the mechanisms of host cell invasion and parasite immune evasion, as well as immune cell trafficking during leishmaniasis in order to develop vaccines and novel therapeutics for this disease. Dr. Satoskar’s laboratory has demonstrated a critical role of IL-17 in mediating susceptibility and controlling immunopathology during visceral leishmaniasis (VL). They have also identified an unexpected role of STAT1 in mediating susceptibility and organ pathology in this infection. Other studies from his laboratory have demonstrated critical roles of chemokine receptors CCR1 and CXCR3 in regulating outcome of cutaneous leishmaniasis (CL). Recent generation of CXCR3-EGFP reporter mice and T cell-specific CXCR3 transgenic mice in Dr. Satoskar’s laboratory have revealed functionally distinct novel subsets of immune cells and have opened new avenues of research. The other area of research in Dr. Satoskar’s lab focuses on translation studies to develop better therapeutics for treatment of CL. In collaboration with University of Campeche, Mexico, and Drs. Doug Kinghorn and Jim Fuchs at OSU, School of Pharmacy, Dr. Satoskar’s group has identified two novel antileishmanial compounds from the plant P. andreuxii which has been used by Mayan traditional healers to treat CL for centuries. In addition, his group was the first one to demonstrate use of topical radio-frequency induced therapy for treatment antimony-refractory-CL in HIV infected patients in India. Additional multicenter clinical studies are planned with collaborators in India, Ethiopia, Peru and Guatemala to compare efficacy of RF therapy versus conventional antimonial treatment. An emerging interest in Dr. Satoskar’s lab is understanding the role of macrophage migration inhibitory factor (MIF) in cancer. The studies in collaboration with Dr. Oberyszyn have revealed a novel role of MIF in development UV-induced inflammation and skin cancer, and studies with an industrial partner are ongoing to evaluate efficacy of novel MIF antagonists in prevention and/or treatment of these cancers.