Cryptococcosis Serotypes Impact Outcome and Provide Evidence of Cryptococcus neoformans Speciation

Abstract

Cryptococcus neoformans is a human opportunistic fungal pathogen causing severe disseminated meningoencephalitis, mostly in patients with cellular immune defects. This species is divided into three serotypes: A, D, and the AD hybrid. Our objectives were to compare population structures of serotype A and D clinical isolates and to assess whether infections with AD hybrids differ from infections with the other serotypes. For this purpose, we analyzed 483 isolates and the corresponding clinical data from 234 patients enrolled during the CryptoA/D study or the nationwide survey on cryptococcosis in France. Isolates were characterized in terms of ploidy, serotype, mating type, and genotype, utilizing flow cytometry, serotype- and mating type-specific PCR amplifications, and multilocus sequence typing (MLST) methods. Our results suggest that C. neoformans serotypes A and D have different routes of multiplication (primarily clonal expansion versus recombination events for serotype A and serotype D, respectively) and important genomic differences. Cryptococcosis includes a high proportion of proven or probable infections (21.5%) due to a mixture of genotypes, serotypes, and/or ploidies. Multivariate analysis showed that parameters independently associated with failure to achieve cerebrospinal fluid (CSF) sterilization by week 2 were a high serum antigen titer, the lack of flucytosine during induction therapy, and the occurrence of mixed infection, while infections caused by AD hybrids were more likely to be associated with CSF sterilization. Our study provides additional evidence for the possible speciation of C. neoformans var. neoformans and grubii and highlights the importance of careful characterization of causative isolates.

Cryptococcus neoformans isolates from Yaoundé human immunodeficiency virus-infected patients exhibited intra-individual genetic diversity and variation in antifungal susceptibility profiles between isolates from the same patient

“…There is no published value for the ECV of ketoconazole on C. neoformans (Pfaller et al, 2011;Espinel-Ingroff et al, 2012a, b). (Desnos-Ollivier 2015). Another speculation is that genetic variations in an initial strain allow for a better adaptation within the host organism (Illnait-Zaragozí et al, 2010b).…”

“…Cryptococcus neoformans is a human opportunistic fungal pathogen causing severe disseminated meningoencephalitis, mostly in immunocompromised patients (Desnos-Ollivier et al, 2015). The incidence of cryptococcal meningitis has increased since the advent of human immunodeficiency virus (HIV) infection (Jain et al, 2005;Casadevall, 2010).…”

“…The MLST method has been applied on large sets of cryptococcal isolates covering the complete C. gattii/C. neoformans species complex (Hagen et al, 2012;Cogliati et al, 2013;Kaocharoen et al, 2013;Chen et al, 2015;Desnos-Ollivier et al, 2015), but this technique is laborious, has a long turnaround time and is associated with significant costs. Microsatellites are increasingly popular moleculartyping targets, since they provide cost-effective genotyping with fast turnaround times.…”

Fungal serotype-specific differences in bacterial-yeast interactions

“…13 Furthermore, recent molecular evidence suggests the possible speciation of Cn serotypes A and D and underscores the careful characterization of strains belonging to these varieties. 16 Cn's interactions with countless soil predators influences the evolution of virulence factors associated with enhanced survival in competitive environments. 17 One example of a soil predator is Acinetobacter baumannii (Ab), a Gram negative, free-living saprophyte found ubiquitously in nature.…”

Discovery and Characterization of a Peptoid with Antifungal Activity against Cryptococcus neoformans

“…29 Having demonstrated the initial antifungal potency of AEC5, we sought to further evaluate this property by determining the MIC of AEC5 against other serotypes and strains of C. neoformans; namely, the serotype D lab strain (ATCC 24067), two serotype A clinical isolates (B18 and B24), 30 and two serotype D clinical isolates (AD 12−27 and AD 12−30). 31 The MIC of AEC5 against all these organisms ranged from 6.3 to 25 μg/mL, while the IC 50 ranged from 0.68 to 12.2 μg/mL (Table 1 and Figure S3). Given that serotypes A and D are 15% different genetically 32 and the composition of the cell walls are likely different, 33,34 it is not surprising that this compound is not as potent against clinical isolates of serotype D.…”