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A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent

Johanna Rhodes1, Mathew A Beale2, Mathieu Vanhove1

  • 1Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom.

G3 (Bethesda, Md.)
|February 12, 2017
PubMed

Insights

Recurrent cryptococcal meningitis in HIV/AIDS patients is often relapse, not reinfection. Whole-genome sequencing revealed novel mutations causing a hypermutator state, enabling rapid evolution and antifungal drug resistance in Cryptococcus neoformans.

Area of Science:

  • Mycology
  • Genetics
  • Infectious Diseases

Background:

  • Recurrent cryptococcal meningitis (CM) is a significant cause of mortality in HIV/AIDS patients, particularly in sub-Saharan Africa.
  • Distinguishing between relapse from the original infection and reinfection with a new isolate is crucial for effective treatment and management.

Purpose of the Study:

  • To investigate the genetic basis of recurrent CM in HIV-infected individuals.
  • To determine whether recurrence is due to relapse of the original Cryptococcus neoformans isolate or reinfection with a different isolate.

Main Methods:

  • Whole-genome sequencing (WGS) was employed to analyze paired isolates from 17 HIV-infected individuals with recurrent CM.
  • Genetic comparisons were made between isolates obtained before and after recurrence.

Main Results:

  • Fifteen out of 17 pairs of isolates showed a clonal relationship, indicating relapse of the original infection.
  • Two pairs exhibited high genetic heterogeneity. One was due to mixed genotype infection, and the other resulted from nonsense mutations in DNA mismatch repair genes (MSH2, MSH5, RAD5).
  • These mutations induced a hypermutator state in C. neoformans, increasing substitution rates and potentially facilitating rapid within-host evolution and antifungal drug resistance.

Conclusions:

  • Recurrence of CM in this cohort was predominantly due to relapse of the original Cryptococcus neoformans infection.
  • Novel nonsense mutations in DNA mismatch repair genes can lead to a hypermutator phenotype in C. neoformans.
  • This hypermutator state represents a new mechanism for rapid within-host adaptation and the evolution of antifungal drug resistance in C. neoformans, with significant implications for patient outcomes.
Keywords:
cryptococcosisevolutiongenomicshypermutationresistance

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