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Senior Staff

Karen M. Frank, MD, PhD

Karen M. Frank, MD, PhD, D(ABMM)
Chief, Microbiology Service
Department of Laboratory Medicine

Academic Degrees
MD, PhD, University of Pennsylvania

Email: karen.frank@nih.gov

Phone: 301-402-9559

Biosketch

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 laboratory of Dr. Fred Alt at the Boston Children's Hospital.

Academic Biosketch

Dr. Frank is a board-certified Clinical Pathologist, with twelve years experience as a clinical microbiologist and five years of experience as Director of Clinical Microbiology & Immunology Laboratories. She served as Director of the Lab Service Center and Phlebotomy, and as an Associate Director of a Pathology Residency Program. Dr. Frank serves on the Resident In-Service Exam Committee of the American Society of Clinical Pathology, has served on the executive council 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. She is involved in both translational and basic science projects. Translational projects include an evaluation of MALDI-TOF identification of microorganisms and molecular methods for viral detection in transplant patients. The basic science project involves the investigation of the mechanism of lung injury due to Staphylococcus aureus alpha-hemolysin using a murine model of pneumonia. She joined the Department of Laboratory Medicine in the Clinical Center at NIH in 2012.

Clinical Interests

The Microbiology Service is a CAP-accredited 7000 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 throughout the world, some with very rare disorders, and many of the patients are extremely 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 meet daily with the infectious diseases physicians and have 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 multiple investigators, with Nocardia/rapidly growing mycobacterial and the human skin microbiome being two examples of such projects.

Research Interests

The focus of Dr. Frank's current research is the pathogenesis of Staphylococcus aureus pneumonia. She has collaborated with Dr. Julie Bubeck-Wardenburg in the Departments of Pediatrics and Microbiology at the University of Chicago.

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. Neutralization of key virulence factors is one approach to find effective therapeutic agents to combat Staphylococcal infections. Another approach to therapy is the modulation of host response; therefore, a better understanding of host susceptibility to Staphylococcal infection is needed to combat infections due to this organism. It is not clear which Staphylococcal genes are most critical for virulence or which host responses are more directly involved in recovery. 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. These data provide a complete expression profile at four and at twenty-four hours post-infection, revealing a unique response to the toxin-expressing strain. Gene ontogeny analysis revealed significant differences in the extracellular matrix and cardiomyopathy pathways, both of which govern cellular interactions in the tissue microenvironment. Following up on the observation of an upregulation of the p19 subunit of interleukin-23, we determined that the cellular immune response to infection was characterized by a prominent Th17 response to the wild-type pathogen. These findings define specific host mRNA responses to Hla-producing S. aureus, coupling the pulmonary Th17 response to the secretion of this cytotoxin. Expression profiling to define the host response to a single virulence factor proved to be a valuable tool in identifying pathways for further investigation in S. aureus pneumonia. This approach may be broadly applicable to the study of bacterial toxins, defining host pathways that can be targeted to mitigate toxin-induced disease.

By investigating the host-pathogen interaction and the pathogenesis of Staphylococcal lung injury, our ultimate goal is to further the development of novel therapeutic approaches for Staphylococcal disease.

Honors & Awards

Paul E. Strandjord Young Investigator Award, Academy of Clinical Laboratory Physicians & Scientists, 1998; Life Science Research Foundation Award/Howard Hughes Medical Institute, 1996-97; NIH/NIAID K08 Award, 1997-2002; American Cancer Society, Institutional Research Grant, 2000-01; Cancer Research Foundation Young Investigator Award, 2001-2; HHMI Biomedical Research Support Program to support lab start-up. Award to Univ. of Chicago, P.I., Dr. Godfrey Getz, 2001-03; Robert Leet & Clara Guthrie Patterson Trust Award, 2001; AACR/National Foundation for Cancer Research Career Development Award, 2001-03; Kimmel Foundation Scholar Award, 2001-03; American Cancer Society Illinois Division Research Award, 2002; University of Chicago Cancer Research Foundation Auxiliary Board, 2003-06.

Selected References

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.

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., *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.

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.

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.

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.

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.

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., Zhou, T., Moreno-Vinasco, L., Hollett, B., Garcia, J. G. N., and Bubeck Wardenburg, J., Host Response to Staphylococcal Alpha-Toxin Implicates Pulmonary Th17 Response. Infect. Imm., 2012, In press.

This page last reviewed on 10/15/12



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