Resistance of Asian Cryptococcus neoformans Serotype A Is Confined to Few Microsatellite Genotypes

Abstract

Background Cryptococcus neoformans is a pathogenic yeast that causes cryptococcosis, a life threatening disease. The prevalence of cryptococcosis in Asia has been rising after the onset of the AIDS epidemic and estimates indicate more than 120 cases per 1,000 HIV-infected individuals per year. Almost all cryptococcal disease cases in both immunocompromised and immunocompetent patients in Asia are caused by C. neoformans var. grubii . Epidemiological studies on C. neoformans in pan-Asia have not been reported. The present work studies the genetic diversity of the fungus by microsatellite typing and susceptibility analysis of approximately 500 isolates from seven Asian countries. Methodology/Principal Findings Genetic diversity of Asian isolates of C. neoformans was determined using microsatellite analysis with nine microsatellite markers. The analysis revealed eight microsatellite complexes (MCs) which showed different distributions among geographically defined populations. A correlation between MCs and HIV-status was observed. Microsatellite complex 2 was mainly associated with isolates from HIV-negative patients, whereas MC8 was associated with those from HIV-positive patients. Most isolates were susceptible to amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole, but 17 (3.4%) and 10 (2%) were found to be resistant to 5-flucytosine and fluconazole, respectively. Importantly, five Indonesian isolates (approximately 12.5% from all Indonesian isolates investigated and 1% from the total studied isolates) were resistant to both antifungals. The majority of 5-flucytosine resistant isolates belonged to MC17. Conclusions The findings showed a different distribution of genotypes of C. neoformans var. grubii isolates from various countries in Asia, as well as a correlation of the microsatellite genotypes with the original source of the strains and resistance to 5-flucytosine.

Extensive Genetic Diversity within the Dutch Clinical Cryptococcus neoformans Population

“…High MICs remain exceptional; a few were found, including for the two isolates from CSF and blood from the same patient, with at least a 4 log 2 dilution difference in MIC of flucytosine (8 and Ͼ64 g/ ml). In our collection, flucytosine resistance was rare, but there are countries where it is emerging, such as Indonesia (34). Nine isolates were less susceptible for fluconazole, while all other antifungal compounds inhibited the growth of C. neoformans.…”

IP3-4kinase Arg1 regulates cell wall homeostasis and surface architecture to promoteCryptococcus neoformansinfection in a mouse model

“…Amphotericin B exhibits significant haematological and nephrological toxicity 4 , while echinocandins are ineffective against the Cryptococcus complex 5,6 . Furthermore, fluconazole-resistant C. neoformans has been reported in Sub-Saharan Africa and South East Asia 7,8 . A detailed understanding of the biology of C. neoformans and other pathogenic fungi is essential for the identification of new drug targets.…”

Molecular epidemiology of Cryptococcus neoformans and Cryptococcus gattii in China between 2007 and 2013 using multilocus sequence typing and the DiversiLab system

“…gattii species complex, such as karyotype analysis [15], polymerase chain reaction (PCR) fingerprinting by using M13 [10,16], restriction fragment length polymorphism of the gene URA5 (URA5-RFLP) [10,[17][18][19], AFLP [20,21], random amplification of polymorphic DNA (RAPD) [16], multilocus sequence typing (MLST) [9,11,22], and multilocus microsatellite typing (MLMT) [23], etc.…”