Research Abstract:
My lab focuses on the basis for mucosal immunity, inflammation, and remodeling, especially in relation to lung disease. We concentrate on the response to respiratory viruses, since these agents are most commonly associated with acute and chronic obstructive lung diseases. We use viral, cellular, and mouse models as well as human subjects for study, and we take advantage of genomics, genetics, immunology, virology, and cell biology. Our approach aims to determine which factors control acute viral infection and how transient infections cause chronic airway disease. We have shown that viral immunity depends on a special network of immune-response genes in epithelial cells, macrophages, and dendritic cells, and these signals are being refined as targets for antiviral strategies. Viruses also permanently activate an alternative immune axis that depends on NKT cells and macrophages to drive chronic inflammatory lung disease. The immune and genetic basis for this effect is being defined in a mouse system that can be extended to patients with chronic lung disease. |
Selected Publications:
Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, Benoit LA, Byers DE, Alevy Y, Tucker J, Swanson S, Tidwell R, Tyner JW, Morton JD, Castro M, Polineni D, Patterson GA, Schwendener RA, Allard JD, Peltz G, and Holtzman MJ. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 2008 14: 633-640.
Grayson MH, Cheung D, Rohlfing MM, Kitchens R, Spiegel DE, Tucker J, Battaile J, Alevy Y, Yan L, Agapov E, Kim EY, and Holtzman MJ. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med 2007 204: 2759-2769.
Tyner JW, Kim EY, Ide K, Pelletier MR, Roswit WT, Morton JD, Battaile JT, Patel AC, Patterson GA, Castro M, Spoor MS, You Y, Brody SL, and Holtzman MJ. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest 2006 116: 309-321.
Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, O'Sullivan MP, Walter MJ, Schwendener RA, Cook DN, Danoff TM, and Holtzman MJ. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nat Med 2005 11: 1180-1187.
Zhang Y, Takami K, Lo MS, Huang G, Yu Q, Roswit WT, and Holtzman MJ. Modification of the STAT1 SH2 domain broadly improves interferon efficacy in proportion to p300/CBP coactivator recruitment. J Biol Chem 2005 280: 34306-34315. (Selected as Paper of the Week, see J Biol Chem 2005 280:e99946) |