William M. Mitchell, M.D., Ph.D.
Innate immunity, cancer diagnostics, intracellular pathogen discovery and analysis
Current active areas of investigation include the following:
1. Innate immunity initiated by Activation of Toll-Like Receptor 3 (TLR3). The TLRs are microbial pattern recognition proteins that initiate innate immune responses to microbial invasion. TLR3 is unique among the 10 human TLRs in its intracellular signaling pathways and reduced inflammatory responses. Agonists of TLR3 and response elements are being examined as viral inhibitors and next generation immune vaccine enhancers (super adjuvants) with reduced adverse advents in humans. We have investigated efficacy against highly pathogenic avian influenza viruses in humans (HPIVh) including H5N1 and oseltamivir resistant H7N9 as well as seasonal influenza vaccines with activity against HPIVh.
2. Next Generation Sequencing (NGS) applications. We have used a variety of NGS platforms to develop new diagnostic massively parallel sequencing methods for the real time evaluation of efficacy of cancer therapy using plasma/serum analysis of DNA from apoptotic neoplastic cells.
3. Pathogenesis of human intracellular pathogens. Our current focus is on the pathogenesis of latency of two microorganisms: a) Chlamydia pneumoniae is a recently recognized member of the genus Chlamydia. This obligate intracellular bacterium has been recently linked to a variety of human idopathic inflammatory diseases. C. pneumoniae is an obligate intracellular pathogen which lacks a mechanism for generating energy and relies on the host cell mitochondria as an energy source. We have developed improved methods for detection (culture, immunoassay, and PCR) of this microbe in human tissue and blood. The organism is difficult to eradicate since elements of the immune system (IFN) and/or antibiotics induce the acquisition of a stringent response in which the organism stops replication and enters an anaerobic phase which we refer to as a cryptic or latent phase. Reactivation of the cryptic phase yields a resumption of replication. b) Human immunodeficiency virus (HIV) is the etiological agent of the Acquired Immunodeficiency Syndrome (AIDS). Current studies are focused on HIV latency. Latent HIV provirus integrated into the human genome of memory B lymphocytes provide silent sites of reactivation not susceptible to current anti-retroviral therapy (ART). Strategies involve activation of provirus by TLR3 agonists and interferon with ART control of infection to eliminate proviral foci of latent infection.