Karen M. Frank, MD, PhD, D(ABMM)
Chief, Microbiology Service
Department of Laboratory Medicine
MD, PhD, University of Pennsylvania
Education / Background
Dr. Frank completed her M.D. and Ph.D. in Biochemistry at the University of Pennsylvania. She completed a Clinical Pathology Residency at the Brigham & Women's Hospital. During her postdoctoral research fellowship in Immunology, she focused on V(D)J recombination in developing lymphocytes in the HHMI laboratory of Dr. Fred Alt at the Boston Children's Hospital. As a faculty member, her studies included DNA repair mechanisms relevant to both cancer and immunology, followed by microbiological investigations of Staphylococcus aureus and Enterobacteriaceae.
Dr. Frank is a board-certified Clinical Pathologist, with 14 years experience as a clinical microbiologist and seven years of experience as Director of Clinical Microbiology and/or Immunology Laboratories. She previously served as Director of the Lab Service Center and Phlebotomy, and as an Associate Director of a Pathology Residency Program. Dr. Frank chairs the Resident In-Service Exam Committee of the American Society of Clinical Pathology, she is President-Elect of the Academy of Clinical Laboratory Physicians and Scientists, and has been the Director of an ACGME-accredited Clinical Microbiology Fellowship. She has served as a consultant for medical student education and clinical algorithms for bacterial antibiotic resistance testing in the laboratories of two hospitals in China as part of the Wuhan Medical Education Reform Project. Laboratory projects include an evaluation of MALDI-TOF identification of microorganisms and molecular methods for microbial identification. She joined the Department of Laboratory Medicine in the Clinical Center at NIH in 2012.
The Microbiology Service is a CAP-accredited 7,000 square foot laboratory, offering tests that cover all areas of microbiology, including bacteriology, mycology, parasitology, mycobacteriology, and virology. We provide testing for many NIH institute research programs and we therefore have state-of-the-art instrumentation, including an extensive molecular diagnostics section and a BSL3 level facility. The laboratory staff have consistently published peer-reviewed studies for many years. This laboratory was one of the leading laboratories in the United States to investigate the use of MALDI-TOF technology for organism identification and to integrate the technology into the routine daily workflow. We have more than 26 full-time microbiology staff, primarily licensed medical technologists, as well as four senior level microbiology staff positions to oversee all of the sections of the laboratory. The Clinical Center serves as a medical center only for patients enrolled in clinical trials, and because of this unique mission, the patients enrolled come from locations throughout the world, some with very rare disorders, and many of the patients are very immunocompromised. Therefore, the laboratory has access to a wide variety of specimens from diverse populations, including organisms that are not routinely isolated in many hospital settings. The senior staff in the microbiology laboratory meets daily with the infectious diseases physicians and has routine interactions with the scientists leading the clinical trials, providing a great environment for further investigation of antibacterial resistance. Collaborative research is conducted on campus with investigators from multiple NIH institutes.
Dr. Frank's research collaboration with Dr. Julie Bubeck-Wardenburg in the Departments of Pediatrics and Microbiology at the University of Chicago focused on the pathogenesis of Staphylococcus aureus pneumonia. Pneumonia due to Staphylococcus aureus causes significant morbidity and mortality in both children and adults. Although Staphylocccous aureus is known to have a number of virulence factors, the essential factors involved in lower respiratory tract disease are not yet completely understood. The alpha-hemolysin of Staphylococcus aureus has been identified through animal models of pneumonia as one of the critical virulence factors for lung injury.
Using microarray analysis of murine lung RNA, we examined the response of the host to a virulent Staphylococcal strain compared to a strain deficient in the alpha-toxin. We determined that the cellular immune response to infection was characterized by a prominent TH17 response to the wild-type pathogen. Investigation of the host-pathogen interaction and the pathogenesis of Staphylococcal lung injury will contribute to programs aimed at the development of novel therapeutic approaches for Staphylococcal disease.
Resistant Gram Negative Bacteria
Antibiotic-resistant bacteria cause significant morbidity and mortality in hospitalized patients, causing the Centers for Disease Control and Prevention to list carbapenem-resistant bacteria as a urgent threat requiring attention by the medical community.
Investigators in the National Human Genome Research Institute and the Clinical Center have used advanced DNA sequencing methods to characterize carbapenem-resistant Enterobacteriaceae in hospitalized patients. They tracked a cluster of infections in hospitalized patients, then more recently, we conducted a two year follow-up study to understand the possible spread of the resistant genes between bacteria on plasmids, the genetic material which encodes antibiotic resistant genes in these bacteria.
Advanced sequencing is a valuable technique to aid the infection control team in learning how to control the spread of multi-drug resistant bacteria between critically ill patients at the NIH Clinical Center as a model for healthcare systems. Improved understanding of the genetic basis of antibiotic resistant bacteria guides further strategies to rein in antibiotic resistance and focus experiments directed toward improved treatment for these serious infections.
To further investigate the mechanisms used by bacteria to spread resistance, we examined the frequency of horizontal gene transfer among species, using bacterial isolates from two hospitals. Most conjugation studies use a lab strain of E. coli, typically under narrow conditions. Given that conjugation is influenced by multiple factors, we sought to perform a systematic analysis of blaKPC encoding plasmids transfer into multiple species.
The efficiency of conjugation into Enterobacteriaceae patient isolates and a common lab cloning E. coli strain ranged widely from high rates of 10-2 or 10-3 CFU transconjugants/CFU recipients to undetectable, without a clear correlation with the pattern of spread suggested during two hospital outbreaks. In vitro models may not faithfully predict plasmid mobilization until we better understand the most important variables affecting conjugation efficiency. Additional studies will be valuable in assessing the role of conjugation in the worldwide spread of resistance as compared to other factors contributing to the success of epidemic clones.
Pauli N.T., Kim H.K., Falugi F., Huang M., Dulac J., Dunand C.H.., Zheng N.Y., Kaur K., Andrews S.F., Huang Y., DeDent A., Frank K.M., Charnot-Katsikas A., Schneewind O., Wilson P.C. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J Exp Med. Oct 27. pii: jem.20141404, 2014.
Haspel R.L, Rinder H.M., Frank K.M., Wagner J., Ali A.M., Fisher P.B., Parks E.R.; Training Residents in Genomics (TRIG) Working Group. The current state of resident training in genomic pathology: a comprehensive analysis using the resident in-service examination. Am. J. Clin. Pathol. 142:445-51, 2014.
Conlan S., Thomas P.J., Deming C., Park M., Lau A.F., Dekker J.P.., Snitkin E.S., Clark T.A., Luong K., Song Y., Tsai Y.C., Boitano M., Dayal J., Brooks S.Y., Schmidt B., Young A.C., Thomas J.W., Bouffard G.G., Blakesley R.W.; NISC Comparative Sequencing Program, Mullikin J.C., Korlach J., Henderson D.K., Frank K.M., Palmore T.N., Segre J.A. Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae. Sci.Transl. Med. 6:254ra126. doi: 10.1126/scitranslmed.3009845., 2014.
Lau, A.F., H. Wang, R.A. Weingarten, S.K. Drake, A.F. Suffredini, M.K. Garfield, Y. Chen, M. Gucek, J-H Youn, F. Stock, H. Tso, J. DeLeo, J.J. Cimino, K.M. Frank, & J.P. Dekker, A Rapid Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based Method for Single-Plasmid Tracking in an Outbreak of Carbapenem-Resistant Enterobacteriaceae. J. Clin. Microbiol. 52:2804-12, 2014.
Iida N., Dzutsev A., Stewart C.A., Smith L., Bouladoux N., Weingarten R.A., Molina D.A., Salcedo R., Back T., Cramer S., Dai R.M., Kiu H., Cardone M., Naik S., Patri A.K., Wang E., Marincola F.M., Frank K.M., Belkaid Y., Trinchieri G., Goldszmid R.S. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:967-70, 2013.
Charnot-Katsikas, A., Tesic, V, Boonlayangoor, S., Bethel, C, and Frank, K.M. Prospective Evaluation of the VITEK MS for the Routine Identification of Bacteria and Yeast in the Clinical Microbiology Laboratory: Assessment of Accuracy of Identification and Turnaround Time. J. Med. Microbiol. 63:235-41, 2013.
Frank, K. M., Zhou, T., Moreno-Vinasco, L., Hollett, B., Garcia, J. G. N., and Bubeck Wardenburg, J.,Host response signature to Staphylococcus aureus alpha-hemolysin implicates pulmonary Th17 response, Infect. Immun. 80:3161-3169, 2012.
Inoshima, I., Inoshima, N., Wilke, G., Powers, M., Frank, K., Wang, Y., and Bubeck Wardenburg, J., A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection, Nature Medicine 17:1310-1314, 2011.
Frank, K. M., Schneewind, O., and Shieh, W. J. Investigation of a researcher's death due to septicemic plague. N. Engl. J. Med. 364:2563-2564, 2011.
Inoshima, I., Inoshima, N., Wilke, G., Powers, M., Frank, K., Wang, Y., and Bubeck Wardenburg, J., A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med. 17:1310-1314, 2011.
Frank, K. M., Hogarth, D. K., Miller, J. L., Mandal, S., Mease, P. J., Samulski, R. J., Weisgerber, G. A., and Hart, J., Investigation of the cause of death in a gene-therapy trial. N. Engl. J. Med. 361:161-169, 2009.
Charnot-Katsikas A., Dorafshar A. H, Aycock J. K, David M. Z,. Weber S. G., Frank K. M., Two Cases of Necrotizing Fasciitis Due to Acinetobacter baumannii. J Clin. Microbiol. 47:258-63, 2009.
Woo, L.L., Futami, K., Simamoto, A., Furuichi, Y., and Frank, K.M., The Rothmund-Thomson Gene Product, RECQL4, Localizes to the Nucleolus in Response to Oxidative Stress. Exp. Cell Res. 312:3443-3457, 2006.
Foster, R.E, Nnakwe, C, Woo, L, and Frank, K.M., Monoubiquitination of the nonhomologous end joining protein XRCC4. Biochem Biophys Res Commun. 341:175-183, 2006.
*Frank, K. M., *Sharpless, N. E., Gao, Y., Sekiguchi, J. M., Ferguson, D. O., Zhu, C., Manis, J. P., Horner, J., DePinho, R. A., and Alt, F. W. DNA ligase IV-deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Molec. Cell, 5:993-1002, 2000. *These authors contributed equally.
Gao, Y., Sun, Y., Frank, K. M., Dikkes, P., Fujiwara, Y., Seidl, K. J., Sekiguchi, J. M., Rathbun, G. A., Swat, W., Wang, J., Bronson, R. T., Malynn, B. A., Bryans, M., Zhu, C., Chaudhuri, J., Davidson, L., Ferrini, R., Stamato, T., Orkin, S. H., Greenburg, M. E., and Alt, F. W. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell, 95:891-902, 1998.
*Frank, K. M., *Sekiguchi, J. M., Seidl, K. J., Swat, W., Rathbun, G. A., Cheng, H.-L., Davidson, L., Kangaloo, L., and Alt, F. W. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature, 396:173-177, 1998. *These authors contributed equally.