UTMB Department of Pathology

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Cellular Signal Transduction in Viral Pathogenesis

My laboratory is engaged in research into the processes of cellular signal transduction and their role in disease pathogenesis. I study the role of cellular transcription factors in normal cellular signal transduction in an effort to understand how alterations in these systems lead to or contribute to diseases such as cancer and infectious diseases

Lassa Fever, and many other hemorrhagic fever viruses as well as West Nile virus are on the select list of bioterrorist threat agents. The molecular mechanisms by which Arenaviruses induce hemorrhagic fever are unknown, preventing the design and implementation of novel clinical interventions and therapeutics for treatment. The pathogenesis of these diseases is believed to involve inappropriate production of pro-inflammatory cytokines. Dysregulation of the immune response relates to our demonstration that virus-induced changes in cell signaling appear to contribute to this pathogenetic sequence. It is our long-term goal to understand how hemorrhagic fever viruses alter host cell signaling leading to immune modulation, pathogenic consequences and disease. We seek to identify the viral proteins and the means by which they modulate the host response to Arenavirus infections, thereby, ultimately seeking new anti-arenaviral therapeutics, and to develop novel strategies to suppress the elaboration of pathogenic mediators. We are employing a variety of experimental approaches including proteomics and genomics to identify potential cellular signaling pathways altered by arenaviruses. In various collaborations, we are using high throughput methodologies to identify novel therapeutics to correct these Arenavirus induced host cell changes. This includes our collaborative development of thioaptamers targeting transcription factors that are important regulators of the immune response. We have evidence that we can protect animals from the fatal consequences of some viral infections by modulating the activities of specific cellular transcription factors.

I have a long-standing interest into the functions of the NK-kB/Rel family of transcription factors. Cytokines, bacteria, viruses, parasites, oxidative stress and many other stimuli activate these factors. NFkB/Rel proteins are key regulators of the host response to pathogens. Dysregulation of the host response frequently results in pathologies associated with infections.

There are specific qualitative and quantitative changes in NF-kB/Rel proteins in cultured macrophages and in macrophages derived from animal infected by virulent Pichinde virus but not with the avirulent virus. I (in collaboration with Dr. Aronson) am in the process of defining the mechanisms of change in the NF-kB/Rel proteins and their influence on pathogenesis of these arenaviruses. In collaboration with my colleagues (Drs. Aronson, Gorenstein and Luxon) I am developing decoy oligonucleotides to titrate out different dimers of NF-kB/Rel proteins and AP-1 proteins that modulate the expression of proinflammatory cytokines in response to Pichinde virus infection and in an animal model of sepsis in an effort to reduce pathogenesis and to more precisely define which genes each dimer regulates. I hope to generate novel anti-viral compounds to treat viral infections such as those which cause fatal hemorrhagic fevers. I am also developing a novel proteomics chip to monitor transcription factor activities.

1. Bassett, SE, Fennewald, SM, King, DJ, Li, X, Herzog, NK, Shope, RE, Aronson, JF, Luxon, BA, Gorenstein, DG. Combinatorial selection and edited combinatorial selection of phosphorothioate aptamers targeting human NF-kB RelA/p50 and RelA/RelA. Biochemistry 43(28): 9105-9115, 2004
2. Yang,X, Li, X, Prow TW, Reese, LM, Bassett S, Luxon, BA, Herzog, NK, Aronson, J, Shope, RE, Leary, JF, Gorenstein, DG Immunofluorescence assay and flow cytometry selection of bead bound aptamers. Nucleic Acids Research 31(10): 1-8 2003
3. King, DJ, Basset, SE, Herzog, NK, Shope, RS, Fennewald, SA, Luxon, BA, Gorenstein, DG. Combinatorial selection and binding of phosphorothioate aptamers targeting human NF-kB RelA(p65) and p50 Biochemistry 41:9696-9706 2002
4. Fennewald, SM, Aronson, JF Zhang L, Herzog, NK Alterations in NFkB and RBP-Jk by Arenavirus Infection of Macrophages in vitro and in vivo. J. Virol. 76(3):1154-1162 2002
5. Yang,X, Bassett,S, Li, X, Luxon, BA, Herzog, NK, Shope, RE, Aronson, J, Prow, TW, Leary, JF, Romy, K, Ellington, A, Gorenstein, DG Construction and Selection of bead-bound combinatorial oligonucleoside phosphorothioate and phosphorodithioate aptamer libraries designed for rapid PCR-based sequencing. Nucleic Acids Research 30(23):e132 2002
6. Volk DE, Yang, X,. Fennewald, SM, King, DJ, Bassett, SE, Venkitachalam, S, Herzog NK, Luxon, BA and Gorenstein, DG. Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-kB. Bioorganic Chemistry 30 396-419 2002.
7. Kain, K.H., Popov, S., Herzog, NK A role for the mitochondrial transcription factor in regulating respiratory capacity during differentiation Biochimica Biophysica Acta 1494(1-2):91-103 2000
8. Yang, X.-B, Fennewald, S Luxon, BA, Aronson, J, Herzog, NK, Gorenstein, DG. Aptamers containing thymidine 3’-O-phosphorothioates: Synthesis and binding to Nuclear factor-kB. Bioorganic Medicinal Chemistry Letters: 9:3357-3362 1999
9. Dyer, Roy B, Herzog, NK. Differential regulation of NFkB/Rel protein activities during LPS-induced 70Z/3 cell differentiation. In Vitro 23:231-238 1998
10. Dyer, Rex B, Herzog, NK. Utilization of Tris/Tricine polyacrylamide gels in the analysis of peptide/DNA interactions. Biotechniques.25:447-449 1998
11. Elsom, B, Herzog, NK. Comparison of three products for siliconizing glass plates used in gel electrophoresis. Biotechniques, 22:866-868 1997
12. Lin, J, Tao, J, Dyer, Roy B, Herzog, NK, Justement, LB. Kinase-Independent potentiation of B-cell antigen receptor-mediated signal transduction by the protein tyrosine kinase Src. J. Immunology 159:4823-4833 1997
13. DiNovo, BB, Doan, R, Dyer, Roy B., Baron, S, Herzog, NK, Niesel, DW. Treatment of HeLa cells with bacterial water extracts inhibits Shigella flexneri invasion. FEMS Immunol Med Microbiol. 15:149-158. 1996
14. Dyer, RB, Herzog, NK. Immunodepletion in conjunction with EMSA: A novel technique to identify proteins in DNA-binding complexes. Nucleic Acids Res 23:3345-3346, 1995
15. Dyer, RB, Herzog, NK. Isolation of Intact Nuclei for Nuclear Extract Preparation from Fragile B-Lymphocyte Cell Lines. Biotechniques 19:192-195, 1995
16. He, NG, Awasti, S, Srivastava, SK, Chaubey, M, Herzog, NK, Awasti, YC. An inverse relationship between Doxorubicin resistance and expression of GST- in a series of Doxorubicin resistant sublines of the NCI-H69 human small cell lung cancer cell lines. Biochem Arch 11:9-19; 1995
17. Collaco, C, Dyer, RB, Herzog, NK, Niesel, DW. Shigella flexneri-HeLa cell interactions: A putative role for host cell protein kinases. FEMS Immunol Med Microbiol 10:93 100; 1995
18. Aronson, JF, Herzog, NK, Jerrells, TR. Tumor necrosis factor (TNF) plays a role in the pathogenesis of guinea pig arenavirus disease. Am J Trop Med Hyg 52:262 69; 1995
19. Aronson, JF, Herzog, NK, Jerrells, TR. Pathologic and virologic features of arena virus disease in guinea pigs: comparison of two Pichinde virus strains. Am J Pathol 145:228 235; 1994
20. Chaubey, M, Singhal, SS, Awasti, S, Saxena, M, Dyer, RB, Awasti, Y, Herzog, NK. Gender related differences in expression of glutathione-S-transferases in and their induction by butylated hydroxyanisole. Comp Biochem and Physiol 108:311-319; 1994
21. Awasti, S, Sharma, R, Singhal, SS, Herzog, NK, Chaubey, M, Awasti, YC. Modulation of cisplatin cytotoxicity by sulfasalazine. Br J Cancer 70:190-194; 1994
22. Dyer, RB, Collaco, C, Niesel, DW, Herzog, NK. Shigella flexneri invasion of HeLa cells induces kB DNA-binding activity. Infec Immun 61:4427-4433; 1993
23. Bai, W, Singh, BS, Yang, Y, Ramagli, LS, Nash, M, Herzog, NK, Arlinghaus, RB. The physical interaction between p37env mos and tubulin structures. Oncogene, 7:493 500; 1992
24. Gelman, B, Rodriquez, MG, Wen, J, Kumar, S, Campbell, JR, Herzog, NK. Siderotic cerebral macrophages in the acquired immunodeficiency syndrome. Arch Pathol 116:509 516; 1992
25. Herzog, NK, Nash, M, Ramagli, LS, Arlinghaus, RB. V mos protein produced by in vitro translation has protein kinase activity. J Virol 64:3093 3096; 1990
26. Herzog, NK, Ramagli, LS, Khorana, S, Arlinghaus, RB. Evidence for somatic cell expression of the c mos proto oncogene protein. Oncogene 4:1307 1315; 1989
27. Herzog, NK, Singh, B, Elder, J, Lipkin, I, Trauger, RJ, Millette, CF, Goldman, DS, Cooper, GM, Arlinghaus, RB. Identification of the protein product of the c mos proto oncogene in mouse testes. Oncogene 3:225 229; 1988
28. Walro, DS, Herzog, NK, Lim, ML, Bose, Jr, HR. The product of the v rel oncogene is a soluble cytoplasmic protein and has an associated protein kinase activity. J. Virol. 160:433 444; 1987
29. Singh, B, Goldman, B, Hutton, L, Herzog, NK, Arlinghaus, RB. The p55 protein affected by v mos expression is vimentin. J Virol 61:3625 3629; 1987
30. Singh, B, Herzog, NK, Liu, J, Arlinghaus, RB. p37mos encoded by the HT l strain of Moloney murine sarcoma virus has an associated protein kinase activity. Oncogene 3:79 85; 1987
31. Herzog, NK, Bargmann, WJ, Bose, Jr, HR. Oncogene expression in reticuloendotheliosis virus transformed lymphoid cell lines and avian tissues. J Virol 57:371 375; 1986
32. Herzog, NK, Bose, Jr, HR. Expression of the oncogene of avian reticuloendotheliosis virus in E. coli and the identification of the transforming protein in REV T transformed cells. Proc Natl Acad Sci USA, 83:812 816; 1986
33. Herzog, NK, Bargmann, WJ, Moore, BE, Rice, NR, Bose, Jr, HR. The expression of the oncogene of avian reticuloendotheliosis virus in transformed cell lines and avian tissues. In: Genes and Cancer, J.M. Bishop, J.D. Rowley and M. Greaves (eds.), p. 329 337, Alan R. Liss, 1984.
34. Niesel, DW, Herzog, NK. A valuable new technique: Transformation on agarose gels. Focus, October, 1983

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