Adaptive Evolution of Surface Proteins in Microbial Pathogens: Lyme Disease Pathogens (Borreliella sp.) and Human Immunodeficiency Virus Type 1 (HIV-1)
Cell and virion surface proteins are key to the survival and adaptation of microbial pathogens by enabling them to evade host immune responses and to persist in diverse environments. Pathogens respond to host immune pressures with genetic changes in surface proteins through mechanisms including point mutations, recombination, gene duplication and loss, and lateral gene transfer, resulting in novel antigenic variants and antigenic diversity. This continuous adaptation helps pathogens evade host immunity, leading to chronic infections and recurrent disease outbreaks. Understanding these mechanisms is vital for developing effective strategies to combat infectious diseases. This dissertation comprises three chapters exploring the adaptive evolution of surface proteins in pathogens responsible for Lyme Disease and Acquired Immunodeficiency Syndrome (AIDS). The first chapter focused on antigenicity analysis of the VlsE protein in Borreliella bacteria. Conserved regions of VlsE were identified, and two of them were chosen for antibody development due to their strong antigenicity across host species. Four epitope-specific monoclonal antibodies were generated, with potential applications in detecting active Borreliella infections. The second chapter investigated the evolutionary mechanisms of the vls multicopy gene system through both intra- and inter-species analysis. A combination of mechanisms, including diversifying selection, gene duplications and losses, lateral gene transfer, and translocation events, was found to collectively shape the extensive diversity of vls gene system in the Borreliella population. Simulation studies demonstrated that concerted evolution at the vls locus is driven by the interplay of intra-genomic recombination and gene gain and loss events. In the third chapter, the intra-host evolution of the HIV-1 envelope gene (env) was examined using longitudinal and compartmental data from 13 participants. The results revealed distinct evolutionary dynamics in the peripheral blood and central nervous system, indicating viral adaptation to specific compartments driven by immune selection. Recombination was found to be a potent driver of genetic variation in HIV-1 during persistent infection within the host. Overall, this dissertation provides evidence for the adaptive evolution of two critical surface proteins in two microbial pathogens that severely impact human health. Our work established experimental and computational methods to investigate surface proteins in other microbial pathogens. Furthermore, it highlights the significance of recombination as a driving force of adaptive evolution in both bacterial and viral pathogens.
Bioinformatics, Evolution, Pathogenic Microbiology, Adaptive evolution, Borreliella, HIV-1, microbial pathogens, Surface antigen
City University of New York - Graduate Center
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The Graduate School and University Center of The City University of New York