Microbiology and Immunology
Education and Training
Pennsylvania State University, B.S.
Miami University, Ph.D.
University of Maryland, School of Medicine, Postdoctoral study
My research focuses on the ability of pathogens, e.g., Respiratory Syncytial Virus (RSV), and influenza to modulate the host’s innate immune response by altering macrophage differentiation. I have shown that infection of mice and cotton rats with RSV and mice with influenza induce differentiation of macrophages into an alternatively activated phenotype (AAM). In the case of RSV, the induction of AAM produce a “Th2-like” milieu (e.g., IL-4, IL-13, TSLP) in the lungs of mice and are involved in the resolution of RSV-induced lung pathology. A second aspect of my research studies host-oriented approaches as novel therapeutics for pathogens that induce acute lung injury (ALI). By interfering with the host’s innate immune response it may be possible to control the production of potentially damaging cytokines and DAMPs and mitigate the severity of the infection. Recently, I have demonstrated that the TLR4 antagonist, Eritoran, blocks influenza-mediated acute lung injury even when given late in infection.
Innate Immunity, Macrophage, Macrophage differentiation, Alternatively activated macrophage (AAM or M2), Respiratory Syncytial Virus (RSV), Influenza, Toll-like Receptors (TLRs), Acute Lung Injurey (ALI),secondary bacterial infection
Exploring the complex relationships between pathogens and the host immune response, my work has looked at the ability of multiple pathogens to manipulate the immune response by altering macrophage differentiation. In response to potent inflammatory stimuli, e.g., LPS and IFN-g, macrophages become highly microbicidal through production of pro-inflammatory mediators. Although this process may be necessary for clearance of pathogens, an uncontrolled response can also result in serious tissue damage. In contrast, macrophages exposed to IL-4 or IL-13 produce high amounts of anti-inflammatory cytokines, e.g., IL-10, but few pro-inflammatory mediators, and mediate wound healing and responses to helminths. These two macrophage phenotypes, originally referred to as “Classically Activated Macrophages” (“M1”) and “Alternatively Activated Macrophages (AAM)” (“M2”), to infer that they facilitate development of Th1 and Th2 responses, respectively, have very complex mechanisms for their induction and regulation by various pathogens such as respiratory syncytial virus (RSV) and influenza.
Shirey KA, Cole LE, Keegan AD, and Vogel SN. (2008). Francisella tularensis LVS induces macrophage alternative activation as a survival mechanism. J. Immunol. 181:4159-4167. PMC2637804
Shirey K, Pletneva LM, Puche AC, Keegan AD, Prince GA, Blanco JC, and Vogel SN. (2010). Control of RSV-induced lung injury by alternatively activated macrophages is IL-4Ra-. TLR4-, and IFN-b-dependent. Mucosal Immunol. 3:291-300. PMC2875872
Chen WH, Toapanta FR, Shirey KA, Zhang L, Giannelou A, Page C, Frieman MB, Vogel SN, and Cross AS. (2012). Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from influenza. Immunol Lett. 141:227-234. PMC3243824
Shirey KA, Lai W, Pletneva LM, Karp CL, Divanovic S, Blanco JCG, and Vogel SN. (2014) Role of lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology. Mucosal Immunol. 7(3):549-557. PMC3965659
Murray PJ, Allen JE, Biswas S, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege J, Mosser DM, Natoli G, Saeij SP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachet JA, Vogel SN, and Wynn TA. (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14-20. PMC4123412
Several of my contributions to basic science have a translational aspect as potential therapies for use against respiratory pathogens such as RSV and influenza.
Shirey KA, Nhu QM, Yim, KC, Roberts ZJ, Teijaro JT, Farber DL, Blanco JC, and Vogel SN. (2011). The anti- tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-b-mediated antiviral activity in vitro and in vivo. J Leuk Biol. 89:351-57. See accompanying editorial. PMC3040469
Shirey KA, Lai W, Scott AJ et al. (2013) The TLR4 antagonist, Eritoran, protects mice from lethal influenza infection. Nature 497:498-502. PMC3725830 See accompanying podcast interview.
K. A. Shirey, W. Lai, L. M. Pletneva et al. (2014) Agents that increase alternatively activated macrophage differentiation blunt Respiratory Syncytial Virus-mediated lung pathology. J. Leukoc. Biol. 96: 951-955. PMC4226793 See accompanying editorial.
Piao W, Shirey KA, Ru LW et al. (2015). A decoy peptide that disrupts TIRAP recruitment to TLRs protects mice in a murine model of influenza. Cell Reports 11: 1941-1952. PMC4490105
Shirey KA, Lai W, Patel MC et al. (2016). Novel strategies for targeting innate immune responses to influenza. Mucosal Immunol. 9:1173-82. PMC5125448
The following link provides a full list of my published work:
Honors and Awards
2002 Orton K Stark travel award, Dept. Microbiology, Miami University
2003 Graduate Students Association travel award, Miami University
2004 Susan Rockwood Award for excellence in teaching and research, Department of Microbiology, Miami University
2004, 2005 Center for Bioinformatics Research Fellowship, Department of Microbiology, Miami University
2004-2005 Doctoral-Undergraduate Opportunities for Scholarship (DUOS), Miami University
2005 Dissertation Fellowship, Miami University
2006 Travel award, joint meeting of the Soc. Leukocyte Biology/International Endotoxin and Innate Immunity Society, San Antonio, TX
2008 American Society for Microbiology Women’s Career Development Grant
2010 American Association of Immunologists/Invitrogen Trainee Achievement Award
2012 American Association of Immunologists Trainee Abstract Award
2013 The G. Jeanette Thorbecke Award from the Society of Leukocyte Biology
2014 Theresa L. Gioannini Women in Science Award from the International Endotoxin and Innate Immunity Society
2014 ImmunoTools Research Award from ImmunoTools GmbH, Germany