Epidemiological characteristics of cryptococcal meningoencephalitis associated with Cryptococcus neoformans var. grubii from HIV-infected patients in Madagascar : a cross-sectional study

Cryptococcal meningoencephalitis (CM) remains the most prevalent invasive fungal infection worldwide. The main objective of this study was to describe the prevalence of CM and cryptococcal infection in HIV-infected patients in Madagascar. The secondary objectives were to assess the adjusted prevalence of CM according to clinical presentation and patient characteristics, to determine crude 90-day survival according to cryptococcal antigen (CrAg) status and CM, and to identify the genotypes of Cryptococcus clinical isolates. This cross-sectional study was carried out at two urban hospitals in Antananarivo (central highlands) and Toamasina (east coast) between November 2014 and December 2016. Consecutive HIV-infected adults presenting with CD4 cell counts 64200/\u3bcl were enrolled. Lateral flow immunoassays of CrAg were performed on serum for all patients, and on cerebrospinal fluid for patients with CM symptoms. MALDI-ToF MS, ITS sequencing, and determinations of the molecular and mating types of the isolates were performed. Fluconazole is the only drug for CM treatment available in Madagascar. Patients were treated orally, with high doses (1200 mg/day) for 10-12 weeks and then with 200 mg/day. Minimum inhibitory concentrations were determined for amphotericin B, flucytosine, voriconazole and fluconazole in E-tests. Overall prevalence was 13.2% (95% CI 7.9-20.3) for cryptococcal infection and 10.9% (95% CI 6.1-17.5) for CM, among the 129 HIV-infected patients studied. The 90-day mortality rate was 58.8% (10/17) in CrAg-positive patients and 17.9% (20/112) in CrAg-negative patients (p<0.001). The 13 Cryptococcus strains obtained at baseline were all Cryptococcus neoformans var. grubii, genotypes VNI-\u3b1A (3 isolates), VNII-\u3b1A (4 isolates) or hybrid VNI/VNII-\u3b1AA\u3b1 (6 isolates), suggesting high diversity. Two strains acquired fluconazole resistance after four and five months of exposure, respectively. The prevalence of cryptococcosis is high in Madagascar and this serious condition is life-threatening in HIV-infected patients. These findings will be used to raise the awareness of national authorities to strengthen the national HIV/AIDS control program

Environmental distribution of Cryptococcus neoformans and Cryptococcus gattii around the Mediterranean basin

In order to elucidate the distribution of Cryptococcus neoformans and C. gattii in the Mediterranean basin, an extensive environmental survey was carried out during 2012-15. A total of 302 sites located in 12 countries were sampled, 6436 samples from 3765 trees were collected, and 5% of trees were found to be colonized by cryptococcal yeasts. Cryptococcus neoformans was isolated from 177 trees and C. gattii from 13. Cryptococcus neoformans colonized 27% of Ceratonia, 10% of Olea, Platanus and Prunus trees and a lower percentage of other tree genera. The 13 C. gattii isolates were collected from five Eucalyptus, four Ceratonia, two Pinus, and two Olea trees. C. neoformans was distributed all around the Mediterranean basin, whereas C. gattii was isolated in Greece, Southern Italy, and Spain, in agreement with previous findings from both clinical and environmental sources. Among C. neoformans isolates VNI was the prevalent molecular type but VNII, VNIV and VNIII hybrid strains were also isolated. With the exception of a single VGIV isolate, all C. gattii isolates were VGI. The results confirmed the presence of both Cryptococcus species in the Mediterranean environment, and showed that both carob and olive trees represent animportant niche for these yeasts

Fundamental niche prediction of the pathogenic yeasts cryptococcus neoformans and cryptococcus gattii in europe

Fundamental niche prediction of Cryptococcus neoformans and Cryptococcus gattii in Europe is an important tool to understand where these pathogenic yeasts have a high probability to survive in the environment and therefore to identify the areas with high risk of infection. In this study, occurrence data for C. neoformans and C. gattii were compared by MaxEnt software with several bioclimatic conditions as well as with soil characteristics and land use. The results showed that C. gattii distribution can be predicted with high probability along the Mediterranean coast. The analysis of variables showed that its distribution is limited by low temperatures during the coldest season, and by heavy precipitations in the driest season. C. neoformans var. grubii is able to colonize the same areas of C. gattii but is more tolerant to cold winter temperatures and summer precipitations. In contrast, the C. neoformans var. neoformans map was completely different. The best conditions for its survival were displayed in sub-continental areas and not along the Mediterranean coasts. In conclusion, we produced for the first time detailed prediction maps of the species and varieties of the C. neoformans and C. gattii species complex in Europe andMediterranean area

Environment Interactions Contribute to Variation in Melanin Production in the Fungal Pathogen Cryptococcus neoformans

Cryptococcosis is a common opportunistic fungal infection that often disseminates into the central nervous system, leading to meningitis. Production of melanin pigments during infections is one of the most important virulence factors of its causal agent, the human pathogenic yeast Cryptococcus neoformans species complex. However, almost nothing is known about the patterns of variation in melanin production among clinical and environmental strains and the potential effects of such variations on virulence. In this study, we assembled a global collection of C. neoformans var. neoformans strains and investigated their patterns of melanin variation and potential contributors to such variations. Our analyses revealed that genetic differences and genotype-environment interactions explained up to 59% and 43% of the population’s melanin variance respectively, depending on the tested environments. In comparison, environmental factors alone contributed relatively little to melanin variance. We also identified specific changes within the LAC1 gene, whose protein product catalyzes melanin synthesis, to be associated with variable melanin levels. This study provides fresh insights into the origin and evolution of virulence traits in fungal pathogens while highlighting the complex interplay between genetic and environmental factors that lead to phenotypic variance.Peer Reviewe