Accordingly, genomic changes that confer selective advantages enabling their survival and proliferation have been identified in diverse species. Pathogenic organisms encounter a wide array of challenges during infection of the human host, including oxidative and nitrosative stresses from immune cells, nutrient limitation, and high temperature. Microevolution enables rapid adaptation to selective pressures, permitting expansion into new niches and persistence in the face of ever-changing harsh environmental conditions. These data reveal the first molecular insights into how the Cryptococcus neoformans genome changes during infection of humans and the manner in which microevolution progresses in this deadly fungal pathogen. The observed differences suggest the relapse isolate evolved subsequent to penetration of the central nervous system and may have gained dominance following the administration of antifungal therapy. In addition, the deletion mutant displayed altered virulence in the murine model. Gene deletion of the predicted transcriptional regulator produced changes in melanin, capsule, carbon source use, and dissemination in the host, consistent with the phenotype of the relapse isolate. Of these, two key changes are expected to explain the phenotypic differences observed in the relapse isolate: loss of a predicted AT-rich interaction domain protein and changes in copy number of the left and right arms of chromosome 12. Whole-genome sequencing uncovered a clonal relationship, with only a few unique differences. Despite being identical by multilocus sequence typing, the isolates differ phenotypically, exhibiting changes in key virulence factors, nutrient acquisition, metabolic profiles, and the ability to disseminate in an animal model.
#Sequencher serial serial
To investigate the potential contribution of in-host microevolution to persistence and relapse, we have analyzed two serial isolates obtained from a patient with acquired immunodeficiency syndrome who suffered an initial and relapse episode of cryptococcal meningoencephalitis. The opportunistic fungal pathogen Cryptococcus neoformans is a leading cause of mortality among the human immunodeficiency virus/acquired immunodeficiency syndrome population and is known for frequently causing life-threatening relapses.
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