There has been an increase in recognized trans-species movement and human disease from zoonotic viruses, as well as increased concern about intentional design and introduction of zoonotic organisms in bioterrorism. Our ability to respond to such emerging zoonotic-human viruses has been limited by our inability to predict the source, frequency, and mechanisms of virus host-species switching and adaptation. Recent advances in bioinformatics, molecular biology, structural biology, and synthetic biology, provide tools to design, synthetically reconstruct, and test new and emerging pathogens from sequence databases alone. However, development of broadly-applicable platforms strategies for emerging viruses has not occurred, in part due to concerns about possible misuse of synthetic biology and engineered host-range variants. We propose that is an essential mission of the RCEs to demonstrate the safe use and potential of synthetic biology in rapid response platforms. SARS-coronavirus (SARS-CoV) is a category C emerging pathogen that caused severe human disease worldwide. SARS-CoV is proposed to have emerged in humans following trans-species movement of Bat-Coronaviruses (Bat-CoV) that have been identified by sequence but have not been grown in culture. This proposal uses SARS-CoV and zoonotic Bat-CoV to establish platforms for recovery and testing of zoonotic viruses. The proposed program is comprised of four integrated Specific Aims that will design and synthetically reconstruct distinct serogroups of zoonotic bat-CoV from sequence databases, and define the determinants of host-species movement and adaptation in culture, and in young and senescent mouse models. Further, the Aims will develop strategies for stable and universal attenuation of pathogenesis of all coronavirus groups. The established approaches will allow rapid response and control of natural and deliberately designed human coronaviruses, and also will be directly applicable to development of similar specific rapid-response systems for recovery, analysis, attenuation and response to other category A, B, or C emerging pathogens of concern for human disease or bioterrorism.

Public Health Relevance

This program will establish a platform for synthetic reconstruction of emerging zoonotic-human pathogens, using SARS-CoV and zoonotic Bat coronaviruses as a model. The platform will allow testing for determinants of trans-species movement and adaptation. The approaches will allow rapid response and public health interventions for coronaviruses and other pathogens of concern for natural emergence or bioterrorism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-09
Application #
8234184
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2011-03-01
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$520,883
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Smartt, Chelsea T; Shin, Dongyoung; Alto, Barry W (2017) Dengue serotype-specific immune response in Aedes aegypti and Aedes albopictus. Mem Inst Oswaldo Cruz 112:829-837
Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:
Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111
Silva, Laurie A; Dermody, Terence S (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 127:737-749
Elong Ngono, Annie; Chen, Hui-Wen; Tang, William W et al. (2016) Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection. EBioMedicine 13:284-293
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Rowse, Michael; Qiu, Shihong; Tsao, Jun et al. (2016) Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors. ACS Infect Dis 2:47-53
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-236

Showing the most recent 10 out of 387 publications