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bioRxiv · 10.1101/083469

A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection

Rhodes, J.·Beale, M.·Vanhove, M.·Jarvis, J. N.·Kannambath, S.·Simpson, J. A.·Ryan, A.·Meintjes, G.·Harrison, T. S.·Fisher, M.·Bicanic, T.
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Abstract

Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis. Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, whilst the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5 and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and non-synonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in Cryptococcus neoformans and represent a novel pathway for rapid within-host adaptation and evolution of resistance to firstline antifungal drugs.

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Rhodes, J., Beale, M., Vanhove, M., Jarvis, J. N., Kannambath, S., Simpson, J. A., Ryan, A., Meintjes, G., Harrison, T. S., Fisher, M., Bicanic, T.. 2016-10-26. A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection. https://doi.org/10.1101/083469

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