ABSTRACT Candida parapsilosis is becoming a predominant non-albicans cause of invasive candidiasis (IC). Echinocandins are the preferred choice for IC treatment and prophylaxis. Resistance to echinocandins in C. parapsilosis has emerged in several countries, but little is known about the susceptibility profile in China or about mechanisms of resistance. Here, we investigated the echinocandin susceptibilities of 2523 C. parapsilosis isolates collected from China and further explored the resistance mechanism among echinocandin-resistant isolates. Anidulafungin exhibited the highest MICs (MIC50/90, 1 and 2 µg/mL; GM, 0.948 µg/mL), while caspofungin showed better activity (0.5 and 1 µg/mL; 0.498 µg/mL). Significantly higher echinocandin MICs were observed among blood-derived isolates compared to others, especially for caspofungin (GM, 1.348 µg/mL vs 0.478 µg/mL). Isolates from ICU and surgical wards also showed higher MICs. Twenty isolates showed intermediate phenotypes for at least one echinocandin. One was resistant to all three echinocandins, fluconazole and voriconazole, which caused breakthrough IC during long-term exposure to micafungin. WGS revealed this isolate carried a mutation S656P in hotspot1 region of Fks1. Bioinformatics analyses suggested that this mutation might lead to an altered protein conformation. CRISPR Cas9-mediated introduction of this mutation into a susceptible reference C. parapsilosis strain increased MICs of all echinocandins 64-fold, with similar results found in the subspecies, C. orthopsilosis and C. metapsilosis. This is the first report of a multi-azole resistant and pan-echinocandin resistant C. parapsilosis isolate, and the identification of a FKS1S656P conferring pan-echinocandin resistance. Our study underscores the necessity of rigorous management of antifungal use and of monitoring for antifungal susceptibility.

Decreased echinocandin susceptibility in Candida parapsilosis causing candidemia and emergence of a pan-echinocandin resistant case in China

Antibiotic tolerance is the ability of a susceptible population to survive high doses of cidal drugs and has been shown to compromise therapeutic outcomes in bacterial infections. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains largely unknown. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that brain glucose induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits treatment efficacy for cryptococcal meningitis in mice via inhibiting the synthesis of ergosterol, the target of AmB, and promoting the production of inositolphosphorylceramide, which competes with AmB for ergosterol. Furthermore, AmB combined with an inhibitor of fungal-specific inositolphosphorylceramide synthase, aureobasidin A, shows better efficacy against cryptococcal meningitis in mice than do clinically recommended therapies. 

Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis.

Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis. By exploring stationary-phase indicator molecules and developing single-cell tracking strategies, we show that in the lung, AmB persisters are enriched in cryptococcal cells that abundantly produce stationary-phase molecules. The antioxidant ergothioneine plays a specific and key role in AmB persistence, which is conserved in phylogenetically distant fungi. Furthermore, the antidepressant sertraline (SRT) shows potent activity specifically against cryptococcal AmB persisters. Our results provide evidence for and the determinant of AmB-tolerant persister formation in pulmonary cryptococcosis, which has potential clinical significance. 

Fungicide-tolerant persister formation during cryptococcal pulmonary infection.

Cryptococcus neoformans and its sister species Cryptococcus deuterogattii are important human fungal pathogens. Despite their phylogenetically close relationship, these two Cryptococcus pathogens are greatly different in their clinical characteristics. However, the determinants underlying the regulatory differences of their pathogenicity remain largely unknown. Here, we show that the forkhead transcription factor Hcm1 promotes infection in C. neoformans but not in C. deuterogattii. Monitoring in vitro and in vivo fitness outcomes of multiple clinical isolates from the two pathogens indicates that Hcm1 mediates pathogenicity in C. neoformans through its key involvement in oxidative stress defense. By comparison, Hcm1 is not critical for antioxidation in C. deuterogattii. Furthermore, we identified SRX1, which encodes the antioxidant sulfiredoxin, as a conserved target of Hcm1 in two Cryptococcus pathogens. Like HCM1, SRX1 had a greater role in antioxidation in C. neoformans than in C. deuterogattii. Significantly, overexpression of SRX1 can largely rescue the defective pathogenicity caused by the absence of Hcm1 in C. neoformans. Conversely, Srx1 is dispensable for virulence in C. deuterogattii. Overall, our findings demonstrate that the difference in the contribution of the antioxidant sulfiredoxin to oxidative stress defense underlies the Hcm1-mediated regulatory differences of pathogenicity in two closely related pathogens. 

A forkhead transcription factor contributes to the regulatory differences of pathogenicity in closely related fungal pathogens

Global mycosis is still a problem. One of these is the cryptococcal disease. A systemic mycosis brought on by Cryptococcus is called cryptococcosis. Host immunological conditions influence infection with Cryptococcosis. When environmental spores are inhaled by the host, the spores get to the lungs, an infection is created. Alveolar macrophages and other immune cells recognize Cryptococcus in the lung. The initial line of defense against pathogens in the phagolysosome is provided by alveolar macrophages found in the lungs. When the immune system is weak, Cryptococcus uses the evasion system as a molecular interaction with the immune system and persists in the lungs without causing any symptoms such as Factor Transcription, Cell masking, N-glycan structure, Extracellular molecule, and Antioxidant system. The evasion mechanism protects and makes Cryptococcus disseminate throughout the other organs, especially CNS. If Cryptococcus escapes against the host immune system, it will disseminate to other organs, especially Cerebrospinal System by Three mechanisms. There are Trojan Horse, Paracellular, and Transcellular interactions with Blood-Brain Barrier. Disease severity is determined by the Interaction between the host’s immune system and the fungus.

Biomolecular activity of cryptococcus during cryptococcosis: a review of molecular interactions of cryptococcus with human immune system and blood-brain-barrier

Objective To investigate the application value of combined detection of anti-beta 2-glycoprotein I antibody (anti-β2-GPI), anti-cardiolipin antibody (ACL), and lupus anticoagulant (LA) in the diagnosis of patients with antiphospholipid syndrome (APS). Methods 30 APS patients in our hospital between Jan. 2020 and Jan. 2021 were chosen as the experimental group, and 30 healthy persons with normal physical examination during the same period were selected as the control group The anti-β2-GPI and ACL indexes of both groups were detected by enzyme-linked immunosorbent assay (ELISA), with the LA levels tested by modified dilute Russell's viper venom time (dRVVT) and LA ratio calculated. The diagnostic efficacy of single detection and combined detection was analyzed by plotting the receiver operating characteristic (ROC) curve. Results The serum indexes in the experimental group were remarkably higher than those in the control group (P < 0.001). ROC curve analysis suggested that in the diagnosis of APS, the area under the ROC curve by detecting anti-β2-GPI, ACL, LA ratio alone and simultaneously were 0.517, 0.583, 0.683, and 0.817 respectively, and the combined detection of the three had remarkably higher sensitivity and specificity than those of each single detection. Conclusion The indexes of anti-β2-GPI, ACL, and LA ratio were highly expressed in APS patients, and the combined detection of the three has high diagnostic value and can effectively screen and assist the diagnosis of APS.

/pdf/application-value-of-combined-detection-of-anti-b2-gpi-acl-1apk1pw2.pdf

Application Value of Combined Detection of Anti-β2-GPI, ACL, and Lupus Anticoagulant in the Diagnosis of Patients with Antiphospholipid Syndrome

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A forkhead transcription factor contributes to the regulatory differences of pathogenicity in closely related fungal pathogens

Application Value of Combined Detection of Anti-β2-GPI, ACL, and Lupus Anticoagulant in the Diagnosis of Patients with Antiphospholipid Syndrome