HSV-1 is an important human pathogen, with a global prevalence of ~67% according to World Health Organization. In immunocompromised people, such as those with advanced HIV infection, HSV-1 cause more severe symptoms such as encephalitis or keratitis though rarely. Mother-to-infant transmission can occur, though rarely, estimated 1 out of every 10,000 births globally, but can lead to lasting neurologic disability or death. The mosquito-borne Chikungunya virus (CHIKV) of the Togaviridae family is re-emerging as a significant public health threat world-wide. CHIKV causes acute and chronic crippling arthralgia and long-term neurological disorders. The cumulative cases are over 1.8 million, with 436 deaths directly or indirectly related to CHIKV, in Americas since its invasion into the Caribbean in late 2013. This project investigates the physiological roles of a family of poorly understood genes, UBXNs, in controlling HSV-1 and CHIKV infection and disease pathogenesis in mice via genetic, molecular biological, biochemical and immunological approaches, and may ultimately contribute to development of vaccines and therapeutics. We will first examine the changes in disease pathogenesis and antiviral immune responses of gene deficient animals and cells. We will then understand how UBXNs regulate the innate immune system, specifically the stimulator of interferon genes (STING) pathway, to limit viral infection. STING senses cyclic GMP-AMP (cGAMP), a second messenger that is rapidly synthesized by cGAMP synthase (cGAS) in response to viral DNA, and then induces expression of type I IFNs and other antiviral molecules. Our study with West Nile virus (WNV) and other recent studies consistently demonstrate that STING is also important for the control of RNA virus infection in mouse models. The underlying molecular mechanism, however, remain largely unclear. At the end of this project, we hope to address a gap in our knowledge and understanding of the role of STING in innate immunity to RNA viruses and UBXN3B in regulation of STING-mediated innate antiviral immune response, and increase our knowledge in the host immune responses to human viruses of medical significance.

Public Health Relevance

Both herpes simplex virus 1 and Chikungunya virus are human pathogens of public health significance. This project investigates the physiological roles of a family of poorly understood genes, UBXNs, in controlling HSV- 1 and CHIKV infection and disease pathogenesis in mice via genetic, molecular biological, biochemical and immunological approaches, and may ultimately contribute to development of vaccines and therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI132526-03
Application #
9837413
Study Section
Virology - B Study Section (VIRB)
Program Officer
Vazquez-Maldonado, Nancy
Project Start
2019-01-01
Project End
2022-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Wang, Kezhen; Zou, Chunling; Wang, Xiujuan et al. (2018) Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3. PLoS Pathog 14:e1007287
Ma, Jinzhu; Ketkar, Harshada; Geng, Tingting et al. (2018) Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling. Front Microbiol 9:1350
Yang, Long; Wang, Leilei; Ketkar, Harshada et al. (2018) UBXN3B positively regulates STING-mediated antiviral immune responses. Nat Commun 9:2329