Poxviruses include some dangerous emerging or re-emerging pathogens as well as some promising vaccine vectors for infectious diseases and cancers. They are unique among viruses in that they encode a large number of proteins that are dedicated to evading host immune responses. These proteins include secreted inhibitors of cytokines as well as intracellular inhibitors of immune signaling or antiviral factors. The long-term goal of our project is to uncover the mechanisms of poxvirus immune evasion, which will reveal fundamental principles about virus-host interactions and provide knowledge for the development of vaccines and antivirals. The focus of our last funding period was on a secreted poxvirus interleukin-18 (IL-18) binding protein (IL-18BP), which prevents IL-18 from inducing IFN-? production. We have been very productive and accomplished all the specific aims. In addition, we discovered in vaccinia virus (VACV) two intracellular inhibitors of type I interferons (IFN), K1 and C71,2. This is an exciting finding, since K1 and C7 are host-range factors essential for poxviruses replication in mammalian hosts but their mechanism of action has long been a mystery. We hypothesize that K1 and C7 are essential for poxvirus replication due to their inhibition of a critical IFN-inducible antiviral pathway. Therefore uncovering the mechanism of action of K1 and C7 will reveal not only molecular basis for poxvirus host tropism but also critical innate immune defense mechanism against poxviruses. In the next funding cycle, we propose to follow up our discoveries on K1 and C7 and pursue the following aims.
Aim 1. Structure-function analysis of VACV C7 based on crystal structures of C7 family of proteins.
Aim 2. Identify the host antiviral factors that are targeted by K1 and C7.
Aim 3. Determine the in vivo role K1 and C7 play in replication capacity and immunogenicity of VACV.

Public Health Relevance

Pathogenic poxviruses such as variola virus and monkeypox virus remain a dangerous threat to today's largely unimmunized population, while attenuated poxviruses hold great promise as vaccine vectors. Studying poxvirus immune evasion mechanisms will provide knowledge for development of antiviral therapies and poxvirus-vectored vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI079217-05A1
Application #
8632750
Study Section
Virology - B Study Section (VIRB)
Program Officer
Challberg, Mark D
Project Start
2008-09-24
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Krumm, Brian; Meng, Xiangzhi; Xiang, Yan et al. (2015) Crystallization of interleukin-18 for structure-based inhibitor design. Acta Crystallogr F Struct Biol Commun 71:710-7
Kolli, Swapna; Meng, Xiangzhi; Wu, Xiang et al. (2015) Structure-function analysis of vaccinia virus H7 protein reveals a novel phosphoinositide binding fold essential for poxvirus replication. J Virol 89:2209-19
Meng, Xiangzhi; Krumm, Brian; Li, Yongchao et al. (2015) Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins. Proc Natl Acad Sci U S A 112:14858-63
Krumm, Brian; Xiang, Yan; Deng, Junpeng (2014) Structural biology of the IL-1 superfamily: key cytokines in the regulation of immune and inflammatory responses. Protein Sci 23:526-38
Meng, Xiangzhi; Wu, Xiang; Yan, Bo et al. (2013) Analysis of the role of vaccinia virus H7 in virion membrane biogenesis with an H7-deletion mutant. J Virol 87:8247-53
Meng, Xiangzhi; Schoggins, John; Rose, Lloyd et al. (2012) C7L family of poxvirus host range genes inhibits antiviral activities induced by type I interferons and interferon regulatory factor 1. J Virol 86:4538-47
Meng, Xiangzhi; Embry, Addie; Rose, Lloyd et al. (2012) Vaccinia virus A6 is essential for virion membrane biogenesis and localization of virion membrane proteins to sites of virion assembly. J Virol 86:5603-13
Meng, Xiangzhi; Xiang, Yan (2012) Generation and characterization of monoclonal antibodies specific for vaccinia virus. Methods Mol Biol 890:219-32
Wu, Xiang; Meng, Xiangzhi; Yan, Bo et al. (2012) Vaccinia virus virion membrane biogenesis protein A11 associates with viral membranes in a manner that requires the expression of another membrane biogenesis protein, A6. J Virol 86:11276-86
Krumm, Brian; Meng, Xiangzhi; Wang, Zhixin et al. (2012) A unique bivalent binding and inhibition mechanism by the yatapoxvirus interleukin 18 binding protein. PLoS Pathog 8:e1002876

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