| dc.description.abstract | The genomics era has given us powerful tools to probe the molecular basis of disease, but practical constraints have limited their use in certain settings. In particular, underdeveloped research and medical infrastructure in low-resource countries has hampered the study of deadly pathogens and the diseases they cause in these countries. Two such diseases of note are Lassa Fever (LF) and Ebola virus disease (EVD), which have engendered great human cost across West Africa. In this thesis, I present efforts to overcome these constraints, using genomics technologies and computational analysis to better understand the molecular basis of LF and EVD.
In the first project, we performed a genome-wide association study to uncover the role of human genetic variation in susceptibility to Lassa virus infection and LF disease severity, enrolling 533 LF patients and 1986 population controls over a 7 year period in Nigeria and Sierra Leone. Additionally, we employed seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays to assess population-level resistance and potential functional effects of certain variants. We found associations with LF severity at the GRM7, LIF, and LARGE1 loci. This study demonstrates the value of molecular profiling to better understand the progression of elusive diseases, and provides a guide for future human genetics studies in West Africa.
In the second project, we performed a natural history study of Ebola virus (EBOV) infection in 21 rhesus monkeys, employing RNA-seq and developing new tools to profile the host response to infection across 17 tissues during distinct phases of EVD. We identified several tissue-specific and temporal gene expression changes during infection, and developed a novel computational tool which predicted that monocyte presence was correlated with viral load across the many tissues where EBOV was found. Additionally, we profiled patterns of viral variation across tissues to determine the likely dynamics of viral spread, and found that some of these variants impacted fitness in a minigenome system. Altogether, this work shows in unprecedented detail the host-pathogen dynamics in EVD, proposes novel mechanisms of pathogenesis, and further suggests that functionally significant viral variation can emerge early in the infection course.
Overall, this thesis demonstrates the value of genomic tools for studying deadly pathogens and the diseases that they cause. The body of work to follow immediately suggests novel and tractable therapeutic strategies for both diseases. Additionally, the numerous challenges encountered in this work have yielded insights into best practices for future study design, as well as a perspective on what long-term investments low-resource countries will need to implement in order to maximally benefit from
the promise of the genomics era. | |
