Systems Biology Based Projects
The systems biology platform seeks to derive important insights from within complex biological systems. It's proponents argues that reductionist based approaches cannot capture the complexity needed to drive understanding. It's opponents argue that the hypothesis neutral discovery approach provides only observation with no insights, or most importantly, validation. While both sides have valid points, the conflict characterizes the great irony of systems biology: an approach designed to integrate complex data has itself divided the scientific field.
Our approach argues that systems and reductionist based approaches are not antithetical. Instead, we have developed a refined systems based approach that incorporates elements of both. This new methods builds on the standard systems paradigms while adding targeting and expansion modules that incorporate existing knowledge bases as well as both systems and reductionist based validation approaches. Together, the combination provides ample opportunities for extension and expansion to help understand complex biological systems and derive mechanistic insights. We focus on 3 main areas below.
Our approach argues that systems and reductionist based approaches are not antithetical. Instead, we have developed a refined systems based approach that incorporates elements of both. This new methods builds on the standard systems paradigms while adding targeting and expansion modules that incorporate existing knowledge bases as well as both systems and reductionist based validation approaches. Together, the combination provides ample opportunities for extension and expansion to help understand complex biological systems and derive mechanistic insights. We focus on 3 main areas below.
Virus centric
One tenet of our refined systems based approach is to focus on specific contrast as a means to derive insights. For virus centric projects, we can compare and contrast host responses within and between viral families. For example, systems based studies have revealed and expanded roles for coronavirus proteins ORF6 and NSP16 by comparing response differences between wild-type and mutant viruses. Similarly, cross family comparisons between CoVs and influenza viruses have revealed novel antagonism mechanisms that target interferon stimulated genes (ISGs) and antigen presentation pathways. Comparison of lethal and sublethal disease in vivo identified a critical role for the urokinase pathway in survival and tissue damage. Together, the examination of specific contrasts can further define important host-virus interactions that impact infection and disease outcomes.
Host-genetic diversity
While difficult to query, host genetic diversity plays a critical role in the response to respiratory virus infection. Our approach takes advantage of the Collaborative Cross (CC), a panel of recombinant inbred mice derived from eight "founder" strains that capture genetic diversity similar to the human populations. The initial results, based on the Systems Immunogentics (SIG) platform, indicate a wide spectrum of phenotypic outcomes in terms of viral replication, weight loss, lethality, immune infiltration, antibody response, and more. Importantly, these readouts can be dysregulated from each other, allowing fine mapping to define specific genetic components that drive individual phenotypic responses. Importantly, the broad diversity captured in the CC mimics human genetic variation and likely improves translation between mouse and human models. Pilot studies have identified a number of quantitative trait loci associated with the MX1 gene for influenza infection, Trim55 for vascular cuffing, and others that are currently being validated. The completion of the SIG screen for influenza, SARS-CoV, and West Nile virus provides the opportunity to mine these data sets for new insights for many years to come.
Aging
Infectious disease in the context of aging represents an opportunity to explore changes to immunity and gain insights into a leading cause of death among the elderly. Importantly, both SARS and MERS-CoV induce more severe infection and increased mortality in aged human patients. This phenotype is recapitulated in young and aged mouse models, allowing systems based exploration of host virus interaction that change as a product of aging. The goal of these studies is to identify, confirm, and validate host response changes as a product of aging that determine disease outcome. The project also seeks to confirm finding in human models of aging as well as develop treatment options to mitigate enhanced virulence in the aged host.
Emerging Coronavirus Based Studies
The emergence of SARS-CoV, and more recently, MERS-CoV, underscores the continued threat of cross-species transmission events leading to damaging viral outbreaks in humans. With this in mind, our experimental platform seeks to identify and prepare for future emergent coronavirus outbreaks.
Translational Genomics
Using established reverse genetic systems, we have developed a platform to leverage large metagenomics datasets in order to identify pre-pandemic viruses that are threat due to emergence and pathogenic potential. The approach builds viable chimeric viruses that evaluate the ability of the spike/receptor binding ability and/or their viral backbone to mediate disease in human cells and in vivo. These chimeric viruses can also be used to test the efficacy of current and future therapeutics both in vitro and in vivo. Studies with SARS-like viruses SHC014-CoV and WIV1-CoV reveal significant pathogenic potential due to replication in human cells, in vivo pathogenesis, and marginal efficacy of available therapeutics.
Broad-based viral counter measures
In addition to predicting future pre-pandemic strains, our research also seeks to identify broad-based strategies to mitigate CoV disease. Based on common elements of the CoV life cycle, we have developed live-attenuated vaccine and drug platforms that incorporate multiple mechanisms of attenuation including replication defects, fidelity mutations, sensitivity to type I IFN, and augmented immune stimulation. In addition, the screening of orphan drug libraries and other antiviral repositories permits the development of combination therapies that may prove to improved efficacy over single mechanism based approaches.