Viruses are intricate nanoscale structures that have evolved diverse strategies of influencing the immune system to evade detection and prolong residence within their hosts. The resulting virus-related pathophysiology is accompanied by well-intended inflammatory immune responses aimed at rectifying a disrupted homeostasis. The morphology, surface chemistry, and cellular targets of viruses directs this inflammation, which in many instances becomes dysregulated, resulting in a range of pathologies that can be more harmful than the original viral infection itself. Understanding the specific inflammatory triggers that can induce a particular immunological response is therefore essential to the identification and treatment of virus-induced pathologies as well as impact a broad range of inflammation-driven disease states including atherosclerosis and even seasonal allergies. Unfortunately, the specific mechanisms that are responsible for such harmful immune dysregulations are often prohibitively complex and difficult to isolate. Recent advances in biomedical engineering (BME) and nanotechnology now permit unprecedented control over the physical and chemical properties of synthetic nanostructures, which can be designed to mimic the mechanisms of infection utilized by nanoscale pathogens such as viruses. The research objective of this proposal is therefore to engineer virus-mimicking nanostructures that will serve as tools to investigate specific hypotheses of how viruses can generate dysregulated immune responses. As engineering approaches to immunological questions become more commonplace, future students and researchers interested in highly specialized areas of immunology and virology must be encouraged to pursue careers in the field of BME. The educational objective of this proposal therefore implements a multi-pronged high school BME program that exposes students, as well as their parents, to the diverse opportunities made accessible by a career in BME. This proposal aims to expand BME into new specialized fields of biological science by directly demonstrating the benefits of engineering-based techniques and principles.
A key need in the study of viral immunopathology is a customizable, in situ method to probe how specific viral structures, surface chemistries, and biodistributions contribute to virus-induced dysregulation of the immune system. The PI will rationally design a library of virus-mimicking polymeric nanocarriers (NCs) to investigate the basic biochemical and cellular mechanisms that trigger the model immunodysregulatory disorder hemophagocytic lymphohistiocytosis (HLH). HLH can be controllably induced in several mouse models following infection by the lymphocytic choriomeningitic virus (LCMV). Since the polymers are inert and do not elicit inflammatory responses, the NCs can be considered "blank slates" in which a diverse range of molecules and immunostimulants will be incorporated for controlled transport to and activation of specific immune cells. The essential inflammatory mechanisms that induce HLH are poorly understood, and so this system will be simplified by dividing the various inflammatory components within LCMV, such as its glycoprotein envelope or RNA, into separate NCs that mimic the biodistribution and mechanisms of intracellular degradation of the virus. NCs are assembled from block copolymers, and can be engineered into vesicular and filamentous nanostructures, which respectively target diverse and restricted subsets of inflammatory immune cells. Vesicles will probe hypothesized biochemical mechanisms responsible for HLH by inducing controlled systemic cytokine expression and effector T cell activation. The filaments will investigate the specific cellular role of plasmacytoid dendritic cells, which are an inflammatory immune cell population essential to immune responses against LCMV. Through the use of controlled synthetically induced infections, the key LCMV-related inflammatory mechanisms or combinations thereof responsible for HLH will be identified. This work will demonstrate the use of rationally designed nanomaterials to enhance the understanding of how specific inflammatory triggers contribute to immunopathology. Furthermore, data gathered in these studies will provide insight into essential design criteria required for eliciting specific and controlled immunological responses.
