Research Programs

 

 

 

 

 

 

 

 

 

 

 

 

 

Emerging infections: Principles of emergence

Program Leader: Mark Denison

 

Project: Platforms for synthesis and testing of emerging zoonotic viruses

Mark Denison

Vanderbilt University
Ralph Baric

University of North Carolina

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.

Project: A genetic systems approach to host-pathogen interactions in orthopoxvirus infections

Richard Moyer

University of Florida

The orthopoxviruses, smallpox (variola), ectromelia and to a lesser extent monkeypox virus have narrow host ranges but for others (vaccinia and cowpox viruses) the host range is much more extensive. In light of bioterrorism concerns and the question of how viruses "jump" into new host species (both major concerns of SERCEB), it is imperative to study and identify host gene networks that determine and regulate host range. However, little is known about host genes that determine permissiveness, restriction or clinical course of disease. To elucidate such host genes, we will screen a panel of genetically diverse, C57BL/6J and DBA/2J advanced recombinant inbred (BXD ARI) mice for susceptibility to infection beginning with cowpox and ectromelia virus to establish the system and thereafter monkeypox virus. These mice and relevant services are provided by the SAID Core E. The relative permissiveness of a given virus, coupled with the genetic profiling of the infected versus the uninfected animals and an advanced bioinformatic analysis (genenetwork.org) will identify specific host genes/pathways which are critical for resistance/susceptibility of the infections and provide us a better understanding of the relationship between host and pathogen. These results will provide insight into the design of new intervention strategies, new targets for antiviral therapies and provide clues as to how "species jumping" might occur and identify combinations of biomarkers of host susceptibility/resistance genes that can be used for prognostic purposes and a platform for the screening of other pathogens. We propose the following specific aims: