Immunology, Genetics and Translational Research

Autoimmune diseases affect an estimated 14 to 22 million Americans, 75 percent of whom are women. Collectively, these disorders are considered to be the fourth-largest cause of disability among women in the United States. Research within the department is focused on four major autoimmune disorders: type 1 diabetes, scleroderma, rheumatoid arthritis and multiple sclerosis. These efforts include:

• The mapping and identification of genes that play a role in susceptibility to EAE, an animal model of multiple sclerosis in mice and rats
• Making a congenic for the only dominant diabetogenic locus in the rat for positional cloning of the QTL
• Testing a new model for virus-inducible Type 1 diabetes
• Analyzing genetic variants in type III collagen as a risk factor in scleroderma

With respect to scleroderma, current studies are involved in investigating the initiating events of this disease. This has led to the design of novel therapeutics that control extracellular matrix synthesis and thus regulate the fibrotic pathology of this disease. These novel drugs are currently under development or slated for Phase I clinical trials in the near future. Some of these novel therapeutics are immunomodulators, and they could be expanded into therapeutics to treat other autoimmune diseases. Other areas of current active immunology research within the department are focused on dendritic cell (the most potent antigen-presenting cells) biology, functions and immunotherapeutic potential against human chronic viral infections and neuroinflammatory diseases and the neonatal CD8+ T cell response to influenza virus infection.

Malaria

Malaria remains a major health problem in a large part of the world with 300 million cases and 600,000 deaths per year. A major area of research emphasis in the Department of Microbiology & Immunology is focused on various aspects of malarial disease and the challenge it poses to the world. The range of research interests includes basic molecular and cell biological studies, understanding the mechanisms of antimalarial drug action and resistance, studying immunity to malaria and vaccine development, and discovery and development of new antimalarial drugs. A wide range of tools and approaches are used that include bioinformatics, DNA microarrays, yeast two-hybrid screens, and molecular modeling and virtual screening, as well as a variety of other molecular genetic, immunological and biochemical techniques. Researchers at the College represent one of the largest academic groups in the country working to understand, treat and prevent malarial disease.

Microbial Pathogenesis and Genomics

Chronic bacterial pathogenesis: Departmental investigators have been instrumental in developing many of the theoretical constructs now used in modeling of chronic infections. These have been grouped together under the rubric of Bacterial Plurality and include the biofilm paradigm, the distributed genome hypothesis, and the concept of population-level virulence factors. These new paradigms were developed to explain the profound differences between acute and chronic bacterial infections. Chief among these acute:chronic dichotomies is that chronic infections are associated with bacteria having a complex lifecycle and the formation of biofilms.

Many of these studies utilize the application of multiple generations of advanced instrumentation for molecular imaging, molecular diagnostics and next-generation DNA sequencing, which provided for the visualization, detection and complete genomic characterization of vast numbers of unculturable organisms. Studies in this area have classically been in the areas of chronic middle ear disease, chronic sinusitis, cholesteatoma, adenoiditis, tonsilitis, "sterile loosening" of artificial joints, and some cases of osteoarthritis.

Another area of research has been the expansion of pathogenic niches by established pathogens as human behaviors change. In this regard, Haemophilus influenzae, a nasopharyngeal colonizer and infectious agent of the respiratory tree is being studied. Similarly, with the rise of arthroplasties for failed joints we now find that many periodontal pathogens including Treponema denticola, Enterococcus faecalis, Brevundimonas diminuta, and others are associated with periprosthetic joint infections of the knee.

Comparative Bacterial Genomics

Investigators within the group played seminal roles in the development of massively parallel next-generation DNA sequencing, and also in the development of computational pipelines to process and analyze the data returned from such systems. These instrumentation and computational approaches were developed originally to test the distributed genome hypothesis and to model the sizes of the various bacterial species' supragenomes. Initially tested using the pharyngeal pathogens Haemophilus influenzae and Streptococcus pneumoniae, it is now widely accepted that nearly all bacterial species have a supragenome that is far larger than the genome of any single strain, and that the reassortment of genic characters during the polyclonal chronic infectious process generates diversity in situ which provides for improved population survival. Investigators have used core genome data to help with characterizing population substructure within various taxonomic levels, and to help ascertain which strains form natural affinity groups.

Current projects involve the use of statistical analyses and other mathematical approaches to identify unannotated distributed genes that are associated with virulence as a means to use unbiased, top-down approaches to provide targets from within the vast genomic dark matter. This approach has been used successfully with Haemophilus influenzae to uncover a novel family of surface-exposed virulence factors associated with increased invasiveness.

Virology

Investigators working in the Department of Microbiology & Immunology have several areas of research focused around a number of viral pathogens. One of the major focal points involves several lines of research centered on understanding human immunodeficiency virus type 1 (HIV-1) viral genetics, immunopathogenesis, and neurologic disease and the effects of drugs of abuse and aging on these experimental paradigms. To study these questions, departmental investigators working in collaboration with investigators in the Division of Infectious Diseases & HIV Medicine, and other collaborators across the College of Medicine and University at large, have developed a longitudinal cohort of HIV-1-infected patients designated the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Investigators within and outside the Department utilize these patient samples to examine questions surrounding how virus evolution contributes to disease pathogenesis both in the peripheral blood and CNS as well as understanding the viral dynamics of the HIV-1 reservoir and exploring ways to eradicate and "cure" infected patients. The CARES cohort is also utilized to study key questions in understanding how HIV-1 CNS disease and neurologic impairment presents in the era of antiretroviral therapy and to understand metabolic disease as it relates these impairments.

In addition, there are several lines of research focused on understanding HIV-1 viral tropism in immune cells and cells of the CNS, miRNA control of the virus in these cell types, as well as cell trafficking across the blood-brain barrier (BBB) and impact of HIV-1 and drugs of abuse on the BBB. In addition to these avenues of research, members of the Department are also working on understanding physical and immunological factors that impact the risk of male-to-female and female-to-infant HIV-1 transmission. Finally, ongoing research in the Department also encompasses development of novel small molecule inhibitors to HIV both as a therapeutic and in preventing viral transmission. HIV vaccine development for use in prevention and/or prophylaxis is also a research priority. The faculty within and outside of the department along with faculty at Temple University School of Medicine also have two major collaborations that center on a large (NIH/NIMH)-funded T32 training grant for graduate student training in the area of interdisciplinary and translational research training in neuroAIDS as well as the Comprehensive NeuroAIDS Center (CNAC) which is involved in the development of facilities and research resources at Temple and Drexel to assist HIV-1 researchers in their experimental endeavors, with current studies at Drexel centered on the operation of a Research Center of Excellence in International Medicine and Research focused on treatment and prevention of disease caused by HIV-1 subtype C in conjunction with investigators at the Freedom Foundation in Bangalore, India.

Along with HIV, hepatitis B and C (HBV and HCV) are also a main focus of research in the Department. Research in this area focuses on understanding HIV/HCV co-infection, as approximately one-third of HIV-infected persons are co-infected with HBV or HCV. Investigators in the department are interested in defining genetic, immunologic and miRNA control of immune cell responses to treatment in HIV-1/HCV co-infected individuals. In addition, another major focus of departmental investigators is centered on identifying new therapeutics for HBV/HCV infections as well as using state-of-the-art proteomic techniques to elucidate biomarkers of liver cancer in patients. Research in this area also focuses on understanding molecular mechanisms of viral persistence during the course of chronic viral disease this chronic viral infection, viral tropism as it relates to CNS disease, as well as the host immune response to the infection and its contributions to overall disease progression.

Finally, investigators in the Department also conduct research on influenza, coronaviruses and herpes simplex viruses. Specifically, research on influenza focuses on examining the role of CD8+ T cells in the immune response to viral infection and utilizing this knowledge with respect to universal vaccine development. With respect to coronaviruses, investigators in the department are also focused on defining how coronaviruses infect cells, and how viral tropism influences disease as well as in understanding how coronaviruses induce acute self-limited, persistent, as well as fatal infections. In addition, HSV research guided by departmental faculty focuses on the role of the innate and acquired immune responses involved in resisting HSV-1 infection, and how these two components of immunity interact with each other to generate optimal protective responses.