About the Orfeome Project
Viruses encode novel subsets of uncharacterized genes (predicted and hypothetical ORFs and noncoding RNAs) which can be expressed to modulate virus replication efficiency and/or host antiviral responses both in vitro and in vivo. Using highly pathogenic human respiratory and systemic viruses which cause acute and chronic life-threatening disease outcomes, we test the hypothesis that RNA and DNA viruses encode common and unique mechanisms to manipulate virus replication efficiency and host responses to determine severe disease outcomes. To address this hypothesis, the proposal takes advantage of novel expression vector platforms, synthetic gene design, reverse genetics, animal models of human disease, and a defined set of biochemical and immunologic assays to identify, characterize and then determine the role of uncharacterized genes in the lung (e.g., H5N1, SARS-CoV and human coronavirus EMC-1) and in systemic infections (e.g., Ebola and Human Herpes virus 8) both in vitro and in some instances, in vivo. Specifically, we test the hypothesis that these viral uncharacterized genes may function to auto-regulate virus replication efficiency, and/or function as an agonist/antagonize the host intracellular milieu to enhance virus replication, most likely be altering p53, innate immune sensing, inflammasome, apoptosis and/or NFκβ signaling. To achieve these goals, a highly interactive group of experts in RNA and DNA virus pathogenesis and immunity work collectively to create a robust screening platform that rapidly identifies and characterizes the function of these uncharacterized genes in replication and pathogenesis. By identifying common key host bottleneck genes that are targeted by disparate virus pathogens, we identify rationale broadly relevant therapeutic targets for ameliorating disease outcomes in vivo. Importantly, this platform is: a) portable, b) can be rapidly applied to other highly pathogenic respiratory and microbial pathogens, c) will rapidly identify novel targets for therapeutic intervention, d) improve strategies for live attenuated or vectored virus vaccine design, and e) improve global responses to newly identified, epidemic disease outbreaks in human populations.
This project is funded by the National Institute of Allergy and Infectious Diseases under grant U19-AI107810.
The Orfeome project comprises the following organizations:
Most the Baric Lab research has used coronaviruses as models to study the genetics of RNA virus transcription, replication, persistence, and cross species transmission. They have also been using alphavirus vaccine vectors to develop novel candidate vaccines against caliciviruses.
The work in Blossom Damania’s laboratory is focused on understanding the molecular pathogenesis of viral-associated cancers.
The goal of Dirk Dittmer’s research is to understand viral tumorigenesis, specifically, cancers that are caused by Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8).
The Heise laboratory is interested in understanding the interactions between viruses and the infected host that lead either to virus-induced disease or to resolution of the viral infection.
Yohishiro Kawaoka studies the molecular mechanism of interspecies Influenza transmission and the role of viral proteins in the pathogenesis and viral replication of Ebola.