Lee Quinton, PhD

Targeting the Immune System’s Response to Bacterial Pneumonia

Respiratory infection is a leading cause of lung injury and death in the United States. Due to their small size, potentially harmful agents such as bacteria can circumvent initial airway filtration mechanisms, allowing them to invade lower regions of the lung. The body mounts an inflammatory response to bacterial colonization in order to direct the cells of the immune system toward infected airspaces. While this immune response is essential for the clearance of harmful bacteria, it must be precisely regulated in order to prevent lung injury, which can result from excessive inflammation.

Dr. Quinton studied a protein called signal transducer and activator of transcription-3 (STAT3) which is activated within cells during the immune response to lung infection. He hoped to identify factors in the lung that can activate STAT3 and determine the consequence of STAT3 deficiency during bacterial pneumonia.

With the help of his American Lung Association grant, he found that the presence of STAT3 in specific lung cells is required early during infection for promoting inflammation, and is also necessary for limiting inflammation and preventing lung injury at later times. In addition, he identified a previously unrecognized factor that may be most responsible for initiating STAT3 activity in response to lung infection.

The results of this study helped identify specific aspects of the immune system response during pneumonia that can be targeted for therapeutic intervention.

Quinton, L.J., Jones, M.R., Simms, B.T., Kogan, M.S., Robson, B.E., Wilson, C.B., Skerrett, S.J., and Mizgerd, J.P. (2006) Functions and regulation of NF-KB RelA during pneumococcal pneumonia. Journal of Immunology. 178: 1896-1903

Johnston R.A., Mizgerd J.P., Flynt L., Quinton, L.J., Williams E.S., and Shore S.A. (2007) Type I lnterleukin-1 Receptor is Required for Pulmonary Responses to Subacute Ozone Exposure in Mice. A J Respir Cell Mol Biol. 37: 477-484

Happel, K.I., Rudner, X; Quinton, L.J., Movassaghi, J.L., Clark, C., Odden, A.R., Zhang, P., Bagby, G.J., Nelson, S., and Shellito, J.E. (2007) Acute Alcohol Intoxication Suppresses the Pulmonary ELR-Negative CXC Chemokine Response to Lipopolysaccharide. Alcohol. 41: 325-333

Quinton, L.J., Jones, M.R., Robson, B.E., Simms, B.T., Whitsett, J.A., and Mizgerd, J.P. (2008) Alveolar epithelial STATS, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. American Journal of Respiratory Cell and Molecular Biology. 38: 699-706

Gamble, L., Bagby, G.J., Quinton, L.J., Happel, K.I., Mizgerd, J.P., Zhang, P., and Nelson, S. (2008) The systemic and pulmonary lipopolysaccharide binding protein response to intratracheal lipopolysaccharide. Shock 31: 212-7

Quinton, L.J., Jones, M.R., Robson, B.E., and Mizgerd, J.P. (2009) Mechanisms of the hepatic acute phase response during bacterial pneumonia. Infection and Immunity 77: 2417-26

Jones, M.R., Quinton, L.J., Blahna, M.T., Neilson, J.R., Fu, S., Ivanov, A.R., Wolf, D.A., and Mizgerd, J.P. (2009) Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nature Cell Biology 11:1157-63.

Quinton, L.J. and Mizgerd, J.P. (2011) NF-κB and STAT3 signaling hubs for lung innate immunity. Cell and Tissue Research 343(1): 153-65

Pittet, L.A., Quinton, L.J., Yamamoto, K., Robson, B.E., Ferrari, J.D., Algül, H., Schmid, R.M., and Mizgerd, J.P. (2011) Earliest innate immune responses require macrophage RelA during pneumococcal pneumonia. American Journal of Respiratory Cell and Molecular Biology 45(3): 573-81

Zamjahn, J., Quinton, L.J., Mack, J., Frevert, C., Nelson, S., and Bagby, G.J. (2011) Differential flux of macrophage inflammatory protein-2 and cytokineinduced neutrophil chemoattractant from the lung after intrapulmonary delivery. American Journal of Physiology: Lung Cellular and Molecular Biology 301: L568-74

Blahna, M.T., Jones, M.R., Quinton, L.J., Matsuura, K.Y., and Mizgerd, J.P. (2011) The terminal uridyltransferase enzyme zinc finger CCHC domain containing 11 (ZCCHC11) promotes cellular proliferation independent of its uridyltransferase activity. Journal of Biological Chemistry 286(49): 42381-9

Quinton, L.J. (2012) GM-CSF: A double dose of protection during pneumonia. American Journal of Physiology: Lung Cellular and Molecular Biology (Epub ahead of print)

Quinton, L.J., Blahna, M.T., Jones, M.R., Allen, E., Hilliard, K.L., Ferrari, J.D., Zhang, X., Sabharwal, V., Algül, H., Akira, S., Schmid, R.M., Pelton, S.I., Spira, A., and Mizgerd, J.P. (2012) Combined hepatocyte-specific targeting of NF-κB RelA and STAT3 abrogates the acute phase response in mice. Journal of Clinical Investigation 122(5): 1758-63

Quinton, L.J., Mizgerd, J.P., Hilliard, K.L., Jones, M.R., Kwon, C.Y., and Allen, E. (2012) Leukemia inhibitory factor signaling is required for lung protection during pneumonia. Journal of Immunology 188(12): 6300-8

Yamamoto, K., Ferrari, J.D., Cao, Y., Ramirez, M.I., Jones, M.R., Quinton, L.J., and Mizgerd, J.P. (2012) Type I alveolar epithelial cells mount innate immune responses during pneumococcal pneumonia. Journal of Immunology (In Press)