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Title

Computational Genomics of Human-Infecting Microsporidia Species from the Genus Encephalitozoon

Creator

Mascarenhas dos Santos, Anne Caroline

Date

2023

Description

Microsporidia are obligate intracellular pathogens classified as category B priority pathogens by the National Institute of Allergy and...
Show moreMicrosporidia are obligate intracellular pathogens classified as category B priority pathogens by the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH). Microsporidian species from the genus Encephalitozoon infect humans and can cause encephalitis, keratoconjunctivitis or enteric diseases in both immunocompromised and immunocompetent individuals. The main treatment for disseminated microsporidiosis available in the United States is albendazole, an anthelmintic benzimidazole that is also used to treat fungal infections, but species from the Encephalitozoonidae have already shown signs of resistance against this drug. The Encephalitozoonidae harbors highly specialized pathogens with the smallest known eukaryote genomes, with Encephalitozoon cuniculi featuring a genome of only 2.9 Mbp and coding for a proteome of roughly 2,000 proteins. Pathogens are in an everlasting race to quicken their adaptation pace against host defenses. This adaptation is often driven by gene duplication, recombination and/or mutation, and due to the potentially disruptive nature of duplication and recombination processes, many of these evolutions in pathogens are taking place outside conserved genomic loci. As such, genes involved in virulence and drug resistance in pathogens are often localized in the (sub)telomeres rather than in chromosome cores. The small and streamlined nature of microsporidian genomes makes them excellent candidates to investigate the adaptation of pathogens to host defenses, the evolution of their virulence, and the development of their resistance to drugs from a genomic perspective. However, microsporidian genomes are highly divergent at the DNA sequence level and the ones that have been sequenced so far are incomplete and are lacking the telomeres. This high level of sequence divergence hinders standard sequence homology-based functional annotations, blurring our understanding of what these organisms are capable of from a metabolic perspective. The gap in our knowledge of what is encoded in the microsporidia telomeres could lead to an underestimation of their pathogenic capabilities. Therefore, deciphering the functions of unknown proteins in microsporidia genomes and unraveling the content of their telomeres is important to fully assess their potential for adaptability to host defenses and predisposition to drug resistance. Likewise, a better understanding of the genetic diversity in microsporidia will help assess the extent by which host-pathogen interactions are shaping the adaptation of these parasites to humans. As observed in the COVID-19 pandemic, genetic diversity can influence the speed at which pathogens adapt to host defenses and thus can pose a big challenge to disease control. The development of strategies for controlling microsporidiosis outbreaks will likely benefit from the work performed in this thesis. As part of my PhD work, I investigated the virulence and host-adaptation capabilities of human-infecting microsporidia species from the genus Encephalitozoon with computational genomic approaches. This work included: 1) using structural homology to infer the functions of unknown proteins from the microsporidia proteome; 2) sequencing the complete genomes from telomere-to-telomere of three distinct Encephalitozoon spp. (E. cuniculi, E. hellem and E. intestinalis) to determine the genetic makeup of their telomeres and better understand the extent of their diversity; and 3) assessing the intraspecies genetic diversity that exists between Encephalitozoon species.
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