James Kirby Lab
The Kirby Laboratory is interested in understanding bacterial pathogen-host interaction and use insights from this analysis to develop new therapeutic strategies.
There are several lines of active investigation. First, we seek to identify novel antimicrobials that target pathogen-host interaction. Specifically, we are interested in identifying small molecule inhibitors of type IV secretion systems in Gram negative pathogens. These systems are required for virulence in organisms such as Legionella, Brucella, Coxiella, Rickettsia, Anaplasma, Ehrlichia, and Helicobacter. Therefore, we predict these inhibitors should render such organisms avirulent. In doing so, they may serve both as a new type of therapeutic agent -- that blocks virulence rather than directly killing the pathogen per se -- and also as new tools to explore the biology of type IV secretion system-based pathogenesis. To date, we have performed a high throughput screen for such inhibitors in collaboration with the National Screening Reference Laboratory for Biodefense at NERCE-BEID. Several lead candidates and scaffolds have been identified. Experiments are underway to explore structure-activity relationships and characterize activity of these compounds in several infectious model systems.
Second, my laboratory is performing a broader screen to identify compounds that act on the pathogen, pathogen-host interface, and/or host cells to limit intracellular bacterial replication. Related to this project, we recently described a novel high throughput screening technology (highlighted on the cover of the May issue of Assay Development and Technology) to measure contemporaneously and in real-time effects on both intracellular growth of Legionella and host cell viability. This approach has allowed us to rapidly screen approximately 200,000 compounds for intracellular growth inhibition while at the same time weeding out compounds that are toxic to eukaryotic cells. In this way, our screening hits are enriched for those with therapeutic antimicrobial potential.
Third, we are developing high throughput screening technology to identify small molecules that restore antimicrobial susceptibility in multi-drug resistance strains, especially carbapenemase resistant Enterobacteriaceae, an CDC-designated urgent antimicrobial resistance threat.
Fourth, we are exploring pathogen-host interaction amongst Bartonellaceae. Bartonella, a close phylogenetic relative of Brucella, are increasingly recognized as zoonotic human pathogens. Many are exceedingly hard to culture and only identified using sensitive molecular diagnostic techniques, leading to their under-appreciation in human disease. Interestingly, a large array of Bartonella species have adapted to infect and colonize mammalians hosts ranging from rodents to bats to cattle. In fact, they appear to be the most ubiquitous cause of chronic, systemic bacterial infection in mammals, approaching infectious prevalences of 90% in some host species. In contrast to Brucella, Bartonella are spread amongst hosts via blood sucking arthropod vectors. The pathogenic strategies that lead to such successful interaction with hosts and vectors is obviously of great interest. We have been exploring Bartonella pathogenic mechanisms using both in vitro and in vivo systems. It is believed that part of Bartonella's pathogenic strategy takes advantage of an unusual and productive interaction with endothelial cells, the cells that line blood vessels, and presumably contribute to the pathogen's ability to sustain chronic bloodstream infection. Indeed, some species in some hosts have the unusual ability to induce angiogenic tumors, a proliferation of capillaries associated with high local levels of bacteria (i.e., bacillary angiomatosis, verruga peruana, and peliosis hepatis).
Therefore, we have been actively exploring the mechanisms and import of interactions with endothelial cells. Previously, my laboratory showed that Bartonella induces endothelial proliferation in two different ways (PMC123703), both as a potent inhibitor of apoptosis and as a mitogen. We also established the first in vitro model for Bartonella-induced angiogenesis (PMC529148; reviewed in ASM News, 2005, 71(1), 11-12). Multiple additional studies are now underway to investigate how Bartonella manipulates endothelial cells and other attributes of the host milieu to its benefit. For example, we established a murine model for studying chronic Bartonella infection (PMC2877837) in which several important pathologies observed in human infection were recapitulated and are currently being studied. In addition, we have spearheaded a collaborative effort with the Broad Institute, Michael Kosoy (CDC), and several other Bartonella investigators to sequence the genomes of many of the established Bartonella species (see http://www.broadinstitute.org/annotation/genome/Bartonella_group/MultiHome.html). Through use of comparative genomic analysis, this effort is expected to give the Bartonella field many additional insights into this fascinating group of organisms.
The Kirby laboratory is located in the recently built, Center for Life Science in the Longwood Medical Area, Boston, MA (http://www.centerforlifescience.com/). Notably, the CLS Building was the first high-rise laboratory building to receive LEED-Gold Level Certification in the United States (http://lymeproperties.com/center-for-life-science-boston). There is ample natural lighting in our laboratory bays. Academically and physically, we are located within the Pathology Department of the Beth Israel Deaconess Medical Center, a tertiary care medical center associated with Harvard Medical School. The department and institution is highly collaborative and maintains outstanding core facilities that support our research efforts.
James E. Kirby, MD D(ABMM)
Assistant Professor of Pathology, Harvard Medical School
Medical Director, Clinical Microbiology, Beth Israel Deaconess Medical Center
Dr. Kirby received his B.S. degree at Yale University and his M.D. degree from the University of Pennsylvania School of Medicine. He performed pre-doctoral research training in bacterial genetics with Dr. Susan Gottesman at the National Institutes of Health as part of the HHMI-NIH Research Scholars Program. He performed clinical training in Pathology at the Massachusetts General Hospital, where he also served as Chief Resident in Clinical Pathology, followed by a postdoctoral fellowship in bacterial pathogenesis in the Molecular Microbiology Department at the Sackler School of Medicine with Dr. Ralph Isberg, before assuming his present position. In addition to his research activities, Dr. Kirby serves as the Director of the Clinical Microbiology Laboratory at Beth Israel Deaconess Medical Center, and the Director of the Medical Microbiology Fellowship Programs at BIDMC. He is board certified in Clinical Pathology, and is a Diplomat of the American Board of Medical Microbiology. He was the President of the Northeast Branch of the American Society of Microbiology from 2009-2012.
Lucius Chiaraviglio, MS
Mr. Chiaraviglio received his B.S. from Harvard University and M.S. from the University of Chicago. He has worked previously as a systems engineer, programming project consultant, and software test engineer for companies such as Miranova, Laserlith, and Ziatech/Intel, and has been the Principal Investigator for National Science Foundation and California SBIR grants. He has worked in the Kirby Laboratory since 2003.
Yoon-Suk Kang, MS, PhD
Post Doctoral Fellow
Dr. Kang received his Ph.D. from Korea University studying bacterial hydrocarbon degradation by several model organisms in the laboratory of Professor Professor Woojun Park. He then performed postdoctoral work on the genetic regulation of microbial arsenic metabolism in the laboratory of Professor Timothy R. McDermott at the University of Montana. He joined the Kirby Laboratory anti-microbial discovery effort in March 2013.
Postdoctoral Fellow Position available:
Currently seeking a postdoctoral fellow to join multi-faceted high throughput drug discovery and bacterial pathogenesis projects. A doctoral level scientist with experience in microbiology and tissue culture techniques preferred. It is expected that fellows will apply for their own postdoctoral fellowship support concurrent with or prior to joining the laboratory. If interested please email Dr. Kirby ( firstname.lastname@example.org) with an indication of your interests and career goals, and attach a C.V. Also have three letters of support sent to the same email address from mentors who have worked closely with you during your scientific training.