The overarching hypothesis is that P2X7 function contributes to the balance of immune clearance vs. persistence of intracellular pathogens. Using a high-throughput screening assay in whole blood, we have identified two novel P2X7 alleles that alter the channel/pore activity of this receptor. The impact of these polymorphisms on expression patterns and signaling capacity of this receptor is being evaluated in recombinant expression systems. In collaboration with numerous investigators at the UW Asthma Center and the NIH Asthma Clinical Research Network, the influence of these alleles on P2X7 pharmacological responses are being studied in primary alveolar macrophages and respiratory epithelial cells. A rhinovirus infection of epithelial cell model is under development to study effects of P2X7 alleles on the immune responses of these cells.
Loren Clark Denlinger, MD, PhD
600 Highland Avenue
Madison, WI 53792
MD, PhD, Univeristy of Wisconsin
Host-pathogen interactions; the role of macrophages in immunity to intracellular pathogens; innate immune responses like cytokine production & microbial killing amplified by extracellular nucleotide receptor known as P2X7 (significant functional diversity for this receptor exists between cell types & human subjects); role of P2X7 as candidate gene modulating the human innate immune responses of macrophages & airway epithelial cells to Chlamydia pneumoniae, contribution of responses of asthma
Shi L, Manthei DM, Guadarrama AG, Lenertz LY, Denlinger LC. Rhinovirus-induced IL-1β Release from Bronchial Epithelial Cells is Independent of Functional P2X7. Am J Respir Cell Mol Biol. 2012 Apr 5.
Manthei DM, Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Gern JE, Lemanske RF Jr, Denlinger LC. Protection from asthma in a high-risk birth cohort by attenuated P2X(7) function. J Allergy Clin Immunol. 2012 Jun 26.
Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, Woyke T, Allgaier M, Bristow J, Wiener-Kronish JP, Sutherland ER, King TS, Icitovic N, Martin RJ, Calhoun WJ, Castro M, Denlinger LC, Dimango E, Kraft M, Peters SP, Wasserman SI, Wechsler ME, Boushey HA, Lynch SV; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011 Feb;127(2):372-381.e1-3. Epub 2010 Dec 30.
Denlinger LC, Sorkness RL, Lee WM, Evans MD, Wolff MJ, Mathur SK, Crisafi GM, Gaworski KL, Pappas TE, Vrtis RF, Kelly EA, Gern JE, Jarjour NN. Lower airway rhinovirus burden and the seasonal risk of asthma exacerbation. Am J Respir Crit Care Med. 2011 Nov 1;184(9):1007-14.
Guilbert TW, Denlinger LC. Role of infection in the development and exacerbation of asthma. Expert Rev Respir Med. 2010 Feb;4(1):71-83. Review.
Denlinger, L.C., Shi, L., Guadarrama, A., Schell, K., Green, D., Morrin, A., Hogan, K., Sorkness, R., Busse, W.W. and J.E. Gern. Attenuated P2X7 Pore Function as a Risk Factor for Viurs Induced Loss of Asthma Control. Amer. J. Resp. Crit. Care Med. 179:265-70 (PMCID: PMC2643076), 2009.
Maenner, M.J., Denlinger, L.C., Langton, A., Meyers, K.J., Engelman, C.D., and H.G. Skinner. Detecting Gene by Smoking Interactions in a Genome-wide Association Study of Early Onset Coronary Heart Disease Using Random Forests. BMC Genetics, in press, 2009.
Korpi, N.L., Sheerar, D., Urban, C., Guadarrama, A., Schell, K and L.C. Denlinger. 2008. Standardized Method to Minimize Variability in a Functional P2X7 Flow Cytometric Assay for a Multi-Center Clinical Trial . Cytometry: Part B-Clinical Cytometry. 74B:319-329 (PMCID: PMC2622726), 2008.
Walter, M.J., Castro, M., Kunselman, S.J., Chinchilli, V.M., Reno, M. Rumkumar, T.P., Avila, P.C., Boushey, H.A., Ameredes, B.T., Bleeker, E.R., Calhoun, W.J., Cherniack, R.M., Craig, T.J., Denlinger, L.C., Israel, E., Fahy, J.V., Jarjour, N.N., Kraft, M., Lazarus, S.C., Lemanske, Jr., R.F., Martin, R.J., Peters, S.P., Ramsdell, J.W., Sorkness, C.A., Sutherland, R., Szefler, S.J., Wasserman, S.I., and M.E. Wechsler for the NHLBI-Asthma Clinical Research Network. Predicting worsening asthma control following the common cold. Eur Resp J. 32:1548-54 (PMCID2592508), 2008.