Maria Gennaro, PhD
Professor, New Jersey Medical School
Principal Investigator, Public Health Research Institute, New Jersey Medical School
Dr. Gennaro has integrated basic and translational research in her career, with an eye to clinical applications. Her current field of research is tuberculosis, a global infectious disease ranking among the top ten causes of death worldwide. A distinctive aspect of her work has been the research of multidisciplinary solutions to the problems investigated, which has prompted productive collaborations with mathematical modelers, network physicists, bioinformaticians, statisticians, epidemiologists, and clinicians.
In the earlier stages of her career, she contributed to epidemiological studies of infections by Enterobacteriaceae and other bacteria causing diarrheal diseases. She authored the first report on the cloning and nucleotide sequencing of the enterotoxin genes of Vibrio cholerae, the causative agent of cholera. This information was considered critical to the development of new cholera vaccines. When she joined the laboratory of Richard Novick, then the Director of the Public Heath Research Institute and Member of the National Academy of Sciences, her interest shifted to the study of DNA replication in small, multi-copy plasmids of Staphylococcus aureus. These plasmids replicate by the rolling circle mode of replication, which at the time was thought to pertain exclusively to bacterial phages. She discovered two novel genetic elements on plasmids of this group – cmp, a replication enhancer, and pre, a site-specific recombinase, and contributed to the characterization of the plasmid’s origin of replication. When she established her own laboratory, she first continued the characterization of the replication enhancer cmp and of chromosomally encoded proteins that bound to it. At the time, the discovery of a replication enhancer established a new paradigm in biology.
In the mid-eighties, when tuberculosis became rampant in New York City, Dr. Gennaro started working on immunological markers of tuberculosis disease. She first studied the antibody response because antibodies as markers of antigen-specific, adaptive immune responses had the advantages that can be obtained in a minimally invasive way. The contribution of her laboratory has spanned from recognizing that tuberculosis disease is associated with a diverse antibody repertoire, to identifying novel serodominant antigens of M. tuberculosis, devising dedicated rapid serology methods, and eventually characterizing the entire seroreractive immunoproteome of M. tuberculosis using high-throughput screening methods and systems biology data analyses. More recently, she has contributed to the development of RNA flow cytometry, a novel method that achieves high-throughput measurement of single-cell gene expression by combining in-situ nucleic acid hybridization with flow cytometry. Due to its single-cell, multiscale, and multiparameter properties, RNA flow cytometry applied to the analysis of T cell responses is expected to help determine infection stage and therapy response. Her group has developed a semi-automated protocol for RNA flow cytometry, in collaboration with BD Biosciences, which makes it possible to apply this new technology to clinical problems.
Her group also conducts basic research on the interaction between the tubercle bacillus and the host macrophage. By using in vitro and animal models to study stress responses of M. tuberculosis, her group has elucidated key aspects of the transcriptional remodeling of M. tuberculosis during mouse lung infection, including mycobacterial central metabolism and respiratory pathways: these contribute to the identification of targets for antibacterial compounds. Moreover, her group has recently reported a novel envelope stress response system in M. tuberculosis that is also found in other bacteria and also eukaryotic cells, thereby providing a rich example of evolution of the envelope stress response across biological kingdoms. Moreover, her laboratory has reconstructed the full network of regulatory interactions among M. tuberculosis sigma factors, which drive transcriptional remodeling under stress conditions. On the macrophage side, Dr. Gennaro’s laboratory studies the dysregulation of macrophage lipid metabolism in M. tuberculosisinfection, which is central to the formation of the tuberculosis granuloma. Her current research has led to the chemical characterization of the storage lipids found in tuberculous granulomas, on the effects of tuberculosis infection on the host cell’s mevalonate pathway and related antibacterial responses, and on a novel antiadipogenic effect of vitamin D in tuberculosis. Moreover, her group’s discovery that the lipid-lowering statins have antimycobacterial effects when used to treat infected cells has led to demonstrating an adjunctive effect of statins to anti-tuberculosis therapy and opened the way to an NIH-funded clinical trial. Thus, her work has been contributing to the burgeoning area of host-directed tuberculosis therapy.
Dr Gennaro’s research has been funded by the National Science Foundation and by the National Institute of Health. She has also been funded by the Gates-supported Foundation for New and Innovative Diagnostics (FIND), which leads efforts in promoting and implementing translational research for development of TB diagnostics in resource-poor settings. She has served in expert panels to advise the NIH and the World Health Organization in matters related to TB diagnostics, and served in NIH study sections. The PI holds seven patents for proteins and genes useful as vaccines and diagnostic reagents for M. tuberculosis, and in 2009 she was awarded the Thomas Alva Edison Patent Award.