Graduation Date

Spring 5-9-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Immunology, Pathology & Infectious Disease

First Advisor

Mariano Sanchez-Lockhart

Abstract

Marburg virus (MARV) causes a hemorrhagic fever in humans but is asymptomatic in a known reservoir, the Egyptian rousette bat (Rousettus aegyptiacus, ERB). Understanding the mechanisms that drive these different outcomes could potentially advance the development of therapeutics. The immunoglobulin (Ig) response to MARV infection in ERBs in known to serve a roll in protection. The Ig germline encodes Variable (VH), Diversity (DH), and Joining (JH) genes that then recombine (V(D)J) to make up the binding site of an Ig. Understanding the gene composition of the Ig germline is critical to defining the potential B cell repertoire. We hypothesize that the B cell repertoire contributes to the ability of ERBs to overcome MARV infection. However, to study V(D)J rearrangement in ERBs, an accurate annotation of the Ig loci is needed. We constructed one contiguous locus which allowed us to unequivocally define genes and expansions. We described all VH, DH, and JH genes which were only partially annotated or missing entirely in the previous assembly and found an expansion of IGHV genes associated with protection from various pathogens in humans. Strikingly, we found the presence of two functional IgE genes, something not found in any other mammals to date. This is the first complete IGH locus for a bat species and one of only a handful for mammalian species. We conducted in silico functional prediction assays for the Ig isotypes and subclasses to evaluate their theoretical functions and examined components of innate immunity that can interact with Igs. We characterized the B cell receptor (BCR) repertoire of ERBs and defined their B cell diversity mechanism to be somatic hypermutation, which is elevated relative to humans. Finally, we assessed the epitope recognition profile of ERBs to MARV and identified a novel region of recognition that may prevent viral escape which could ultimately protect ERBs from MARV.

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