University of Washington
1705 NE Pacific Street, HSB, K236D
Seattle, WA 98195-7720
Phone: (206) 543-6773
FAX: (206) 543-3050
Host cells recognize the invasion of pathogens and trigger a complex coordinated protective response. The interaction between factors produced by the pathogens and the sensors and cells of the host’s innate and adaptive immune systems is the principal determinant driving the pathogenesis of the vast majority of human infectious diseases. In mammals, inflammation is one of the default responses to invading pathogens, cell damage, or stress. Although being primarily pro-survival, exacerbated inflammatory responses may lead to extensive damage to normal tissues and death of the host. However, the molecular mechanisms underlying severe inflammatory responses to pathogens remain obscure. Of note, excessive inflammatory responses dramatically limit the utility of genetically modified viruses (viral vectors) for human gene therapy applications. In order to advance therapy for infectious and inherited diseases, critical questions related to the understanding of host inflammatory responses must be addressed. Among these important questions are:
My current research is focused on the unraveling of molecular mechanisms that lead to activation of innate immune and inflammatory responses to viral (adenovirus) and microbial (Mycobacterium tuberculosis, Listeria monocytogenes, Salmonella typhimurium) pathogens in mouse models. We believe that this approach, combined with novel state-of-the-art techniques of genomics and proteomics, will continue to generate great insights into the fundamental mechanisms controlling host antiviral and antimicrobial defense systems, tissue homeostasis, and pathogenesis of human inflammatory diseases.
Investigator: Dr. Shayakhmetov is a Research Associate Professor of Medicine (Medical Genetics)
Shayakhmetov D.M., Papayannopoulou T, Stamatoyannopoulos G., and Lieber A. (2000) Efficient gene transfer into human CD34+ cells by a retargeted adenovirus vector. Journal of Virology, v. 74, No 6: 2567-2583.
Shayakhmetov D.M., Carlson C.A., Stecher H., Li Q., Stamatoyannopoulos G., and Lieber A. (2002) A high-capacity, capsid-modified hybrid adeno-AAV vector for stable transduction of human hematopoietic cells. Journal of Virology, v. 76, No. 3: 1135-1143.
Shayakhmetov D.M., Li, Z.-Y., Ni S., Lieber A. (2002) Targeting of adenovirus vectors to tumor cells does not enable efficient transduction of breast cancer metastases.Cancer Research, v. 62: 1063-1068.
Gaggar A, Shayakhmetov D.M., Lieber A. (2003) CD46 is a cellular receptor for group B adenoviruses. Nature Medicine, v. 9(11):1408-12.
Shayakhmetov D.M., Z.-Y. Li, S. Ni, and A. Lieber (2004) Analysis of liver sequestration, transduction of hepatic cells, and innate toxicity after injection of fiber-modified adenovirus vectors. Journal of Virology, V. 78(10): 5368-81.
Shayakhmetov D.M., Li Z.-Y., Gaggar A, Gharwan H, Ternovoi V, Sandig V, and Lieber A. (2004) Genome size determines efficiencies of post-attachment steps and gene transfer of capsid-modified adenovirus vectors in a cell type specific manner. Journal of Virology, V. 78(18):10009-22.
Shayakhmetov D.M., Gaggar A., Ni S., Li Z.-Y., Lieber A. (2005) Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. Journal of Virology, V. 79(12):7478-7491.
Shayakhmetov D.M., Z.-Y. Li, S. Ni, and A. Lieber (2005) Interference with IL-1 signaling pathway improves the toxicity profile of systemically applied adenovirus vectors. Journal of Immunology, V. 175(11): 7310-7319.
Baker A.H., Waddington S.N, Di Paolo N.C., and Shayakhmetov D.M. (2007) The Influence of Blood on In Vivo Adenovirus Bio-distribution and Transduction. Molecular Therapy, 15(8):1410-6.
Di Paolo N.C., Kalyuzhniy O., and Shayakhmetov D.M. (2007) The fiber shaft-chimeric adenovirus vectors lacking the KKTK-motif efficiently infect liver cells in vivo. Journal of Virology, 81(22):12249-59.
Junt T, Moseman EA, Boes M, Fink K, Di Paolo N, Shayakhmetov DM, Mampel T, Whelan SP, von Andrian UH. (2007) Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature, 450(7166):110-114.
Kalyuzhniy O, Di Paolo NC, Silvestry M, Hofherr SE, Barry MA, Stewart PL, Shayakhmetov DM (2008) Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. Proc. Natl. Acad. Sci, USA, 105(14):5483-8.
Di Paolo N.C., van Rooijen N., and Shayakhmetov D.M. (2009) Redundant and synergistic mechanisms control the sequestration of the blood-born adenovirus in the liver. Molecular Therapy, 17(4):675-84.
Di Paolo N.C., Miao E., Aderem A., Kaja M.-K., Flavell R., Iwakura Y., Papayannopoulou T., and Shayakhmetov D.M. (2009) Virus binding to a plasma membrane receptor triggers interleukin-1 α mediated pro-inflammatory macrophage response in vivo. Immunity, 31(1):110-21.
Di Paolo N.C. and Shayakhmetov D.M. (2009) Adenovirus de-targeting from the liver. Current Opinion in Molecular Therapeutics, 11(5):523-31.
Shayakhmetov D.M., Di Paolo, N.C. Mossman, K.L. (2010) Recognition of virus infection and innate host responses to viral gene therapy vectors. Molecular Therapy, in press.