Pathogenic poxviruses such as variola virus and monkeypox virus pose a dangerous threat to today's largely unimmunized population, while attenuated poxviruses hold great promise as vaccine vectors. The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL- 18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. IL-18 is a pleiotropic cytokine that enhances both the innate and acquired immunity [1, 2]. It protects against microbial infection and tumors in murine models. Many poxviruses express an IL-18 binding protein (IL-18BP) that binds to IL-18 with high affinity and inhibits IL-18 mediated immune responses [3-5]. The central hypotheses behind this proposal are that poxvirus IL-18BP greatly affects poxvirus pathogenicity and immunogenicity and that a comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus- based vaccines.
Our specific aims are: 1. To further determine the molecular mechanism by which IL-18BP binds and inhibits IL-18. A detailed understanding of the specific interactions between IL-18, IL-18BP and IL-18 receptor at the molecular level will greatly benefit the development of specific inhibitors against IL-18BP and IL-18 for the treatment of infectious and inflammatory diseases. 2. To develop inhibitors against poxvirus IL-18BP and evaluate the effects of these inhibitors at reducing poxvirus pathogenicity. To determine the spatial requirement of poxvirus IL-18BP in poxvirus pathogenesis. 3. To determine the role of IL-18BP in immunogenicity of poxvirus-based vaccine. This will allow a better understanding of the role of IL-18 in the development of protective immune responses and facilitate the development of a safer and more immunogenic vaccine vector.

Public Health Relevance

The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL-18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. A comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus-based vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079217-04
Application #
8133520
Study Section
Virology - B Study Section (VIRB)
Program Officer
Challberg, Mark D
Project Start
2008-09-24
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$330,784
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Meng, Xiangzhi; Rose, Lloyd; Han, Yue et al. (2017) Vaccinia Virus A6 Is a Two-Domain Protein Requiring a Cognate N-Terminal Domain for Full Viral Membrane Assembly Activity. J Virol 91:
Weisberg, Andrea S; Maruri-Avidal, Liliana; Bisht, Himani et al. (2017) Enigmatic origin of the poxvirus membrane from the endoplasmic reticulum shown by 3D imaging of vaccinia virus assembly mutants. Proc Natl Acad Sci U S A 114:E11001-E11009
Krumm, Brian; Meng, Xiangzhi; Xiang, Yan et al. (2017) Identification of small molecule inhibitors of Interleukin-18. Sci Rep 7:483
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

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