Browsing by Author "Yu, Andy Q."

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    Developing In Vitro and In Vivo Models for Lyme Neuroborreliosis (LNB)
    (2023-08) Alanazi, Fuad Fahad; Yang, X. Frank; Bauer, Margaret E.; Yu, Andy Q.; Relich, Ryan F.; Nass, Richard M.
    Lyme neuroborreliosis (LNB) is a neurologic disorder caused by infection with Borrelia burgdorferi, resulting in inflammation in the central and peripheral nervous systems. LNB remains poorly understood due to the lack of a suitable experimental model. The non-human primate model for LNB presents significant impediments, such as high costs, specialized training, ethical considerations, and low infection frequency. Finding alternative models is imperative to advance LNB research. This study aims to develop alternative in vitro and in vivo models for LNB. First, we developed an in vitro transwell assay to identify the factors required for the blood-brain barrier (BBB) transmigration of B. burgdorferi. Second, we established a middle-aged mouse model for studying neuroinflammation associated with LNB. Last, we further characterized a Caenorhabditis elegans (C. elegans) model to study B. burgdorferi-associated neuron damage. With these models, we discovered that the Rrp2-RpoN-RpoS pathway in B. burgdorferi is essential for B. burgdorferi to cross the BBB and that the outer surface protein C (OspC) controlled by this pathway plays a vital role in crossing the BBB. We found that B. burgdorferi is detectable in the brains of middle-aged mice but not in younger mice and triggers host immune response, resulting in elevated levels of cytokines such as TNF-alpha, IFN-γ, and IL-9 and reduction in microglia in the infected mice. Lastly, we demonstrated that C. elegans can feed on B. burgdorferi, which may result in neurodegeneration. This provides a powerful tool for screening pathogen and host factors involved in neuroborreliosis. Overall, the in vitro and in vivo models developed in this study will significantly advance LNB research, which may lead to the development of new treatments and improved patient outcomes.
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    Identifying Immunological Signatures in Blood Predictive of Host Response to Plasmodium Falciparum Vaccines and Infections Using Computational Methods
    (2023-05) Senkpeil, Leetah Celine; Tran, Tuan M.; Sullivan, William J., Jr.; Yu, Andy Q.; Zhang, Jie
    Malaria infects more than 240 million people every year, causing more than 640,000 deaths in 2021 alone. The complex interactions between the Plasmodium parasites that cause malaria and host immune system have made it difficult to identify specific mechanisms of vaccine-induced and naturally acquired immunity. After more than half a century of research into potential immunization methods, reliable immune correlates of malaria protection still have yet to be identified, and questions underlying the reduced protective efficacy of malaria vaccines in field studies of endemic populations relative to non-endemic populations still remain. In this thesis, I use computational methods to identify biological determinants of whole-parasite vaccine-induced immunity and immune correlates of protection from clinical malaria. Our systems analysis of a PfSPZ Vaccine clinical trial revealed that innate signatures were predictive of increased antibody response but also a decrease in the cytotoxic response required for sterilizing immunity. Conversely, these myeloid signatures predicted protection against parasitemia for subjects receiving a saline placebo, suggesting a role for myeloid-lineage cells in clearing pre-erythrocytic parasite stages. Based on these findings, I created a structural equation model to examine the interactions between cellular, humoral, and transcriptomic responses and the effects these have on protection outcome. This revealed a direct positive effect of CD11+ monocyte-derived cells on parasitemia outcome post-vaccination that was mediated by the presence of P. falciparum-specific antibodies at pre-vaccination baseline. Additionally, this model illustrates an indirect role of CD14+ monocyte activation in restricting immune priming by the PfSPZ Vaccine. Together, this data supports our hypothesis that innate immune activation and antigen presentation are uncoupled from cytotoxic cell-dependent immunity from the PfSPZ Vaccine and that this effect may be antibody-dependent.