GLRCE Therapeutics Development
Research Project 2 : Ebola
Our long-term goal is to develop vaccines and antiviral treatments for Ebolavirus infections. We have developed biologically contained Ebolaviruses that protect mice against challenge with a lethal dose of mouse-adapted Ebolavirus.
In Aim 1, we plan to test the protective efficacy of these Ebolaviruses in guinea pigs and nonhuman primates. Towards drug development, we have established three different high-throughput screening systems that allow screening in BSL-2 containment.
In Aim 2, we propose to conduct high-throughput screening and to optimize lead compounds. The lack of effective preventive or therapeutic treatments for Ebolavirus infections is partly due to the lack of knowledge of cellular genes involved in Ebolavirus replication. Our pilot study demonstrated the potential of siRNA screening approaches to identify such genes; therefore, we plan to conduct siRNA screening of commercially available human siRNA libraries to identify critical genes for the Ebolavirus life cycle
Research Project 4 :Host and bacterial targets mediating immune suppression in pneumonic tularemia
Tularemia is a zoonotic disease caused by Francisella tularensis (Ft.) that is transmitted to humans through tick bites, by direct contact with an infected animal or through accidental (or potentially deliberate) aerosolization. The progression and severity of disease are dependent on the route of entry, immune status of the host and the infecting strain. Four subspecies of Ft have been described: subspecies tularensis (Type A), holarctica (Type B, including the derived live vaccine strain, LVS), novicida, and mediasiatica. Type A strains are the most virulent and are largely restricted to North America. Ft is remarkably infectious when administered through the lungs, requiring as few as 10 viable, aerosolized bacteria to cause a severe, rapidly progressive, and often fatal pneumonia in humans. The bacterium is able to infect and survive within a variety of phagocytic and non-phagocytic cells. It enters cells by receptor-mediated phagocytosis, alters trafficking within the phagosome, and subsequently escapes into the cytosol where it replicates to high numbers. The uncontrolled multiplication of Ft in the host leads to cytotoxicity and release of the bacterium into the surrounding milieu, where it is available to participate in further rounds of cell infection/replication and dissemination throughout the body. Ft activates both bacterial and cell signaling events following its association with the host, and these events largely dictate the extent of disease severity and its progression. It is now increasingly clear from recently published work and preliminary data from this group that the most virulent strains of Ft suppress and/or subvert several aspects of the protective innate immune response in the host which enhances its virulence properties. Therefore, it is essential that these processes be better defined.
Our central hypothesis is that the success of Ft as a human pathogen is linked to its ability to suppress and/or subvert important and specific elements of the protective innate immune response during the early phase of infection. Following immunosuppression, an exuberant inflammatory response ensues which is detrimental to the host. Capitalizing on the discoveries and unique expertise of this group, the AIMS of this RP are to combine genomic platforms with human and rodent cell biologic assays and in vivo systems to:
- Elucidate the major bacterial transcriptional regulators and host molecular mechanisms that mediate virulent Ft entry, intracellular trafficking, antimicrobial responses and initiation of the inflammatory program in the host. We will characterize the extracellular and cytosolic signal transduction molecules and pathways that link these biological processes and identify key molecular targets for intervention.
- Construct, validate, and utilize global microbial and host genetic screening platforms to identify key determinants mediating Ft-induced immune suppression and/or subversion in the host.
