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.
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.
|Mishra, Amarjit; Guo, Yujie; Zhang, Li et al. (2016) A Critical Role for P2X7 Receptor-Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury. J Immunol 197:2828-37|
|Wu, Wenxin; Zhang, Wei; Booth, J Leland et al. (2016) Human primary airway epithelial cells isolated from active smokers have epigenetically impaired antiviral responses. Respir Res 17:111|
|Wang, Lingyan; Li, Wenjun; Li, Shitao (2016) A High Throughput Assay for Screening Host Restriction Factors and Antivirals Targeting Influenza A Virus. Front Microbiol 7:858|
|Wu, Lei; Guo, Xin; Wang, Weiqun et al. (2016) Molecular aspects of Î², Î²-carotene-9', 10'-oxygenase 2 in carotenoid metabolism and diseases. Exp Biol Med (Maywood) 241:1879-1887|
|Sahoo, Kaustuv; Koralege, Rangika S Hikkaduwa; Flynn, Nicholas et al. (2016) Nanoparticle Attachment to Erythrocyte Via the Glycophorin A Targeted ERY1 Ligand Enhances Binding without Impacting Cellular Function. Pharm Res 33:1191-203|
|Patel, Vineet Indrajit; Metcalf, Jordan Patrick (2016) Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge. J Investig Med 64:833-47|
|Rudd, Jennifer M; Ashar, Harshini K; Chow, Vincent Tk et al. (2016) Lethal Synergism between Influenza and Streptococcus pneumoniae. J Infect Pulm Dis 2:|
|Narasaraju, Teluguakula; Harshini, Ashar (2016) Neutrophils as Possible Therapeutic Targets in Severe Influenza Pneumonia. J Infect Pulm Dis 2:|
|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|
|Wu, Wenxin; Zhang, Wei; Duggan, Elizabeth S et al. (2015) RIG-I and TLR3 are both required for maximum interferon induction by influenza virus in human lung alveolar epithelial cells. Virology 482:181-8|
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