RT Journal Article
SR Electronic
T1 A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 083469
DO 10.1101/083469
A1 Johanna Rhodes
A1 Mathew A. Beale
A1 Mathieu Vanhove
A1 Joseph N. Jarvis
A1 Shichina Kannambath
A1 John A. Simpson
A1 Anthea Ryan
A1 Graeme Meintjes
A1 Thomas S. Harrison
A1 Matthew C. Fisher
A1 Tihana Bicanic
YR 2016
UL http://biorxiv.org/content/early/2016/10/26/083469.abstract
AB 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.