Abstract
ABSTRACTThe pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of the genomes of incident and relapse isolates may reveal evidence of determinative, microevolutionary changes within the host. Here, we analyzed serial isolates cultured from cerebrospinal fluid specimens of 18 South African patients with recurrent cryptococcal meningitis. The time between collection of the incident isolates and collection of the relapse isolates ranged from 124 days to 290 days, and the analyses revealed that, during this period within the patients, the isolates underwent several genetic and phenotypic changes. Considering the vast genetic diversity of cryptococcal isolates in sub-Saharan Africa, it was not surprising to find that the relapse isolates had acquired different genetic and correlative phenotypic changes. They exhibited various mechanisms for enhancing virulence, such as growth at 39°C, adaptation to stress, and capsule production; a remarkable amplification of ERG11 at the native and unlinked locus may provide stable resistance to fluconazole. Our data provide a deeper understanding of the microevolution of Cryptococcus species under pressure from antifungal chemotherapy and host immune responses. This investigation clearly suggests a promising strategy to identify novel targets for improved diagnosis, therapy, and prognosis.
Highlights
The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals
Each incident isolate was cultured from a specimen of cerebrospinal fluid (CSF) at the diagnosis of cryptococcal meningoencephalitis but prior to treatment
Relapse isolates were obtained from subsequent CSF specimens more than 120 days following collection of the incident isolate
Summary
The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. We tested the isolates for several key properties related to cryptococcal virulence as well as for their susceptibility to the antifungal drug fluconazole These analyses revealed that the relapsing isolates manifested multiple genetic and chromosomal changes that affected a variety of genes implicated in the pathogenicity of Cryptococcus or resistance to fluconazole. Genes related to catalytic activity and transporters, such as ENA1 and CFO1, were significantly upregulated in cerebrospinal fluid (CSF) during infection, suggesting the importance of such functions for survival of the yeasts in the harsh human environment, within the subarachnoid space [6, 7] These studies identified expression signatures during active infection, they provided only an initial glimpse of how this yeast is able to adapt rapidly and continuously to assault by host immune responses and treatment with antifungal drugs. These studies clearly indicated the importance of microevolution in the adaptation of Cryptococcus to the human CNS and ability to cause disease
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