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Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2016)

HIV/AIDS, malaria, and tuberculosis are the world’s three deadliest infectious diseases of humans, often referred to as the ‘Big Three’. Together, they are responsible for more than 10% of all the deaths worldwide each year. What is perhaps most worrisome is the fact that the current therapies that treat

these conditions are losing their efficacy due to the emergence of antimicrobial drug resistance. Accordingly, research is urgently needed to address the growing problem of drug resistance and to help drive the development of novel therapeutics. In the first chapter of this doctoral dissertation, three strategies to combat drug resistance are discussed: 1. Developing therapeutics that target host-derived factors, 2. Identifying new antimicrobial inhibitors, and 3. Investigating host-pathogen biology using systems analysis to drive the development of novel therapeutics. Examples of research utilizing these strategies are discussed in the following chapters, with a particular focus on two of the “Big Three” pathogens- HIV-1 and the malaria parasite, Plasmodium. The identification and characterization of a novel host factor that regulates HIV-1 reverse transcription is described in Chapter 2. In Chapter 3, the development of a high-throughput phenotypic assay to identify novel antimalarial drugs is discussed, and in Chapter 4, a broad review of systems biology-based research of host-parasite interactions (with an emphasis on Plasmodium) is included. The Appendix includes preliminary data and future aims for systems biology research aimed at understanding Plasmodium liver-stage development. Through the combination of these scientific efforts, we will surely strength our position in the ongoing battle against antimicrobial drug resistance.

  • 5 supplemental files
Cover page: Battling Drug Resistance: A Tale of Two Pathogens
  • Article
  • Peer Reviewed
UCLA Previously Published Works (2015)
Parasitic diseases caused by protozoan pathogens lead to hundreds of thousands of deaths per year in addition to substantial suffering and socioeconomic decline for millions of people worldwide. The lack of effective vaccines coupled with the widespread emergence of drug-resistant parasites necessitates that the research community take an active role in understanding host-parasite infection biology in order to develop improved therapeutics. Recent advances in next-generation sequencing and the rapid development of publicly accessible genomic databases for many human pathogens have facilitated the application of systems biology to the study of host-parasite interactions. Over the past decade, these technologies have led to the discovery of many important biological processes governing parasitic disease. The integration and interpretation of high-throughput -omic data will undoubtedly generate extraordinary insight into host-parasite interaction networks essential to navigate the intricacies of these complex systems. As systems analysis continues to build the foundation for our understanding of host-parasite biology, this will provide the framework necessary to drive drug discovery research forward and accelerate the development of new antiparasitic therapies.
    Cover page: Systems analysis of host–parasite interactions
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2022)
    Viruses must effectively remodel host cellular pathways to replicate and evade immune defenses, and they must do so with limited genomic coding capacity. Targeting post-translational modification (PTM) pathways provides a mechanism by which viruses can broadly and rapidly transform a hostile host environment into a hospitable one. We use mass spectrometry-based proteomics to quantify changes in protein abundance and two PTM types-phosphorylation and ubiquitination-in response to HIV-1 infection with viruses harboring targeted deletions of a subset of HIV-1 genes. PTM analysis reveals a requirement for Aurora kinase activity in HIV-1 infection and identified putative substrates of a phosphatase that is degraded during infection. Finally, we demonstrate that the HIV-1 Vpr protein inhibits histone H1 ubiquitination, leading to defects in DNA repair.
      Cover page: Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2019)
      The exoerythrocytic stage of Plasmodium infection is a critical window for prophylactic intervention. Using genome-wide dual RNA sequencing of flow-sorted infected and uninfected hepatoma cells we show that the human mucosal immunity gene, mucin-13 (MUC13), is strongly upregulated during Plasmodium exoerythrocytic hepatic-stage infection. We confirm MUC13 transcript increases in hepatoma cell lines and primary hepatocytes. In immunofluorescence assays, host MUC13 protein expression distinguishes infected cells from adjacent uninfected cells and shows similar colocalization with parasite biomarkers such as UIS4 and HSP70. We further show that localization patterns are species independent, marking both P. berghei and P. vivax infected cells, and that MUC13 can be used to identify compounds that inhibit parasite replication in hepatocytes. This data provides insights into host-parasite interactions in Plasmodium infection, and demonstrates that a component of host mucosal immunity is reprogrammed during the progression of infection.
        Cover page: Dual RNA-seq identifies human mucosal immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection
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