Joseph P. Mizgerd, Sc.D.
Professor of Medicine and Microbiology
Director, Pulmonary Center
College Education: Amherst College, B.A.
Graduate School: Harvard School of Public Health, Sc.D. in Physiology and Cell Biology
Fellowship: Harvard School of Public Health (C.M. Doerschuk M.D., Pulmonary pathophysiology)
- Acute lower respiratory tract infection
- Innate immunity
- Neutrophil recruitment and activation
- Transcriptional and post-transcriptional regulation of gene expression
Acute lower respiratory tract infections cause a terrible public health burden at present, with potential for worse in the coming years. The outcome of these infections is determined by innate immune responses (such as neutrophil recruitment and activation), necessary for host defense but also contributing to lung injury. Innate immune responses in the lungs require the coordinated expression of diverse mediators including adhesion molecules, chemokines, colony stimulating factors, and cytokines that are absent or present only at low levels in uninfected lungs, but are expressed at high levels during infection. Similar mediators are induced during most lung infections, although individual mediators can have different roles during different infections. The coordinated expression suggests programs of gene regulation. NF-kappaB transcription factors are critical to the gene expression program directing innate immunity in the lungs, with RelA inducing innate immunity genes mediating host defense and p50 counteracting this gene induction to prevent lung injury. Other transcription factors are also important, such as STAT3 which both facilitates host defense and limits lung injury. These transcription factors have cell-specific roles during infection, and elucidating unique cell-specific roles in lung innate immunity is a major ongoing effort. Finally, expression of innate immunity mediators is regulated post-transcriptionally as well. MicroRNAs target innate immunity transcripts, and miRNAs themselves are subject to modifications such as uridylation by Zcchc11 to relieve their repressive activities. An improved knowledge of the molecular mechanisms directing innate immunity in the lungs will provide new directions for preventing and curing acute lower respiratory tract infections.
- Mizgerd JP. 2012. Respiratory infection and the impact of pulmonary immunity on lung health and disease. Am J Respir Crit Care Med (in press).
- Quinton LJ, Blahna MT, Jones MR, Allen E, Ferrari JD, Hilliard KL, Zhang X, Sabharwal V, Algül H, Akira S, Schmid RM, Pelton SI, Spira A, Mizgerd JP. 2012. Hepatocyte-specific mutation of both NF-kappaB RelA and STAT3 abrogates the acute phase response in mice. J Clin Invest 122:1758-1763.
- Yamamoto K, Ferrari JD, Cao YX, Ramirez MI, Jones MR, Quinton LJ, Mizgerd JP. 2012. Type I alveolar epithelial cells mount innate immune responses during pneumococcal pneumonia. J Immunol 189:2450-2459.
- Blahna MT, Jones MR, Quinton LJ, Matsuura K, Mizgerd JP. 2011. Terminal uridyltransferase enzyme Zcchc11 promotes cell proliferation independent of its uridyltransferase activity. J Biol Chem 286:42381-42389.
- Pittet LA, Quinton LJ, Yamamoto K, Robson BE, Ferrari JD, Algül H, Schmid RM, Mizgerd JP. 2011. Earliest innate immune responses require macrophage RelA during pneumococcal pneumonia. Am J Respir Cell Mol Biol 45:573-581.
- Jones MR, Quinton LJ, Blahna MT, Neilson JR, Fu S, Ivanov AR, Wolf DA, Mizgerd JP. 2009. Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nature Cell Biol 11: 1157-63
- Mizgerd, JP. 2008. Mechanisms of disease: Acute lower respiratory infection. N Engl J Med 358:716-727.