Human Respiratory Syncytial Virus (HRSV) is the single largest viral cause of pediatric bronchiolitis and pneumonia. With an estimated mortality of >100,000 children per year woridwide, development of an anti- HRSV vaccine is a priority. Among the current approaches, live-attenuation is attractive because, unlike inactivated vaccines, it promises to induce a broad and balanced immune response. However, live HRSV vaccines have so far been unable to fully prevent potentially dangerous side-effects in infants and children. The long-term objectives of this research are to overcome the safety challenges of live-attenuated HRSV vaccines and to contribute fundamental knowledge ofthe HRSV life cycle to design alternative anti-HRSV approaches. To meet these objectives, this proposal focusses on molecular manipulation of the viral matrix (M) protein to enhance safety of live-attenuated vaccines. The M protein is essential for replication and plays a prominent role in virion-assembly processes, many of which are highly relevant for the production, composition, release, and perhaps stability of virus particles. A better understanding of M functions therefore offers significant potential for vaccine advancements. A novel system was developed based on an infectious virus lacking the M gene (M-null) which allows rapid screening and manipulation of M functions. By providing plasmids expressing M mutants to cells infected with the M-null virus, a preliminary screen identified M mutations with potential to regulate the level of infectious progeny production of a live virus. This proposal utilizes the M-null based system to likewise identify and manipulate assembly-relevant M functions and test the translational potential in vivo, through the following Specific Aims (abbreviated): 1) Identify M functions and mutations, and the underlying mechanisms, that regulate virus assembly, composition, and release. 2) Determine the quality ofthe immune response to live viruses with transmission-deficiencies based on M mutations, in vitro and in vivo. 3) Test promising M mutant viruses for ability to protect mice after challenge with wildtype HRSV. Together these aims will raise our fundamental understanding of HRSV replication and test the potential of M protein manipulation to contribute to the generation of a safe live-attenuated vaccine.

Public Health Relevance

Human Respiratory Syncytial Virus (HRSV) is responsible for the death of >100,000 children each year An anti-HRSV vaccine is a priority but additional knowledge of virus replication and host immunity is needed to impart sufficient safety in a vaccine. This proposal maps and manipulates determinants of virus assembly and transmission and tests the potential to improve the safety of live-attenuated HRSV vaccines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TWD-A (CB))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oklahoma State University Stillwater
United States
Zip Code
Xiao, Xiao; Huang, Chaoqun; Zhao, Chunling et al. (2015) Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition. Arch Biochem Biophys 566:49-57
Guo, Y; Mishra, A; Weng, T et al. (2014) Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death. Cell Death Dis 5:e1286
Huang, Chaoqun; Xiao, Xiao; Chintagari, Narendranath Reddy et al. (2014) MicroRNA and mRNA expression profiling in rat acute respiratory distress syndrome. BMC Med Genomics 7:46