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Treatment strategies for cryptococcal infection: challenges, advances and future outlook
Open accessAbstract
Cryptococcus spp., in particular Cryptococcus neoformans and Cryptococcus gattii, have an enormous impact on human health worldwide. The global burden of cryptococcal meningitis is almost a quarter of a million cases and 181,000 deaths annually, with mortality rates of 100% if infections remain untreated. Despite these alarming statistics, treatment options for cryptococcosis remain limited, with only three major classes of drugs approved for clinical use. Exacerbating the public health burden is the fact that the only new class of antifungal drugs developed in decades, the echinocandins, displays negligible antifungal activity against Cryptococcus spp., and the efficacy of the remaining therapeutics is hampered by host toxicity and pathogen resistance. Here, we describe the current arsenal of antifungal agents and the treatment strategies employed to manage cryptococcal disease. We further elaborate on the recent advances in our understanding of the intrinsic and adaptive resistance mechanisms that are utilized by Cryptococcus spp. to evade therapeutic treatments. Finally, we review potential therapeutic strategies, including combination therapy, the targeting of virulence traits, impairing stress response pathways and modulating host immunity, to effectively treat infections caused by Cryptococcus spp. Overall, understanding of the mechanisms that regulate anti-cryptococcal drug resistance, coupled with advances in genomics technologies and high-throughput screening methodologies, will catalyse innovation and accelerate antifungal drug discovery. Cryptococcosis is a serious fungal infection for which treatment options are limited. In this Review, Cowen and colleagues discuss the current antifungal treatments available for cryptococcal infections, the challenges in developing new treatments, and ongoing efforts to identify novel therapies.
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TL;DR
This review summarizes the limited current arsenal against cryptococcal infection, the intrinsic and adaptive resistance mechanisms used by *Cryptococcus* spp., and emerging therapeutic strategies. It highlights combination therapy, virulence-factor and stress-response targeting, drug repurposing, and immunotherapy/vaccine approaches as promising but still mostly preclinical or early-clinical directions.
Key findings
- Cryptococcal meningitis causes an estimated 223,100 cases and 181,100 deaths annually, with 100% mortality if untreated; only three major antifungal classes are approved, and echinocandins have negligible activity against *Cryptococcus* spp.
- Resistance involves genomic plasticity, including aneuploidy (most commonly chromosome 1 disomy involving *ERG11* and *AFR1*), hypermutator strains with ~200-fold higher mutation rates, and transposon movement; hypermutator *C. gattii* strains showed a 15% higher rate of flucytosine resistance.
- Morphological changes contribute to resistance: thicker capsules and cell walls increase antifungal resistance, and titan cells are defined by >10 µm size, >4C ploidy, a thick cell wall, and a highly crosslinked capsule; ~20% of fungal cells in mouse lungs can become titan cells.
- The phase III amphotericin B plus flucytosine regimen followed by fluconazole reduced 10-week mortality to 24%, compared with ~70% mortality in many low- and middle-income African countries; repurposed sertraline and tamoxifen failed to improve outcomes in later trials.
Methods
- Narrative review synthesizing published literature on cryptococcal treatment, antifungal resistance mechanisms, drug discovery, and immunotherapy; no primary experimental data are reported.
- Evidence discussed includes clinical trials, mouse infection models, genomic and chemical-genetic screens, and high-throughput compound screens, such as >300,000 compounds screened for fungicidal activity and ~3,600 bioactive compounds tested for synergy.
- No systematic search strategy, inclusion criteria, or meta-analysis is described.
Limitations
- Stated in the paper: treatment is limited by intrinsic echinocandin resistance, azole resistance, amphotericin B toxicity, flucytosine resistance and monotherapy limitations, and poor access/cost in resource-limited settings; several promising agents remain preclinical or have failed clinical trials, and 18B7 showed poor cerebrospinal fluid penetration.
- Evident from the text: as a narrative review, it does not provide a systematic or quantitative synthesis, and its conclusions depend on the selected cited literature rather than a predefined review protocol.
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In the paper
“a subset of Cryptococcus isolates have been identified as hypermutator strains30,31, which contain mutations in core genes in the DNA mismatch repair pathway, most notably MSH2 (refs30,32,33)”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [30] Boyce, K. J. et al. Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans. mBio 8, e00595-17 (2017). This report is one of the first of a hypermutator strain in clinical isolates, which has a fitness advantage owing to mutations in mismatch repair genes. source
- Not checked yetcites [31] Boyce, K. J., Cao, C., Xue, C. & Idnurm, A. A spontaneous mutation in DNA polymerase POL3 during in vitro passaging causes a hypermutator phenotype in Cryptococcus species. DNA Repair 86, 102751 (2020). source
- Not checked yetcites [32] Billmyre, R. B., Applen Clancey, S., Li, L. X., Doering, T. L. & Heitman, J. 5-Fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus. Nat. Commun. 11, 127 (2020). source
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In the paper
“a mutation in the proofreading domain of POL3 (encoding the catalytic subunit of DNA polymerase δ) was also shown to confer the hypermutator phenotype31.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [31] Boyce, K. J., Cao, C., Xue, C. & Idnurm, A. A spontaneous mutation in DNA polymerase POL3 during in vitro passaging causes a hypermutator phenotype in Cryptococcus species. DNA Repair 86, 102751 (2020). source
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In the paper
“Laboratory studies have shown that selection for resistance to environmental agrochemicals, primarily through the upregulation of the azole target gene ERG11 and drug efflux pumps, can lead to cross-resistance to clinically deployed antifungals19,20.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms
What the sources say
- Not checked yetcites [19] Bastos, R. W. et al. From the environment to the host: how non-azole agrochemical exposure affects the antifungal susceptibility and virulence of Cryptococcus gattii. Sci. Total Environ. 681, 516–523 (2019). source
- Not checked yetcites [20] Bastos, R. W. et al. Environmental triazole induces cross-resistance to clinical drugs and affects morphophysiology and virulence of Cryptococcus gattii and C. neoformans. Antimicrob. Agents Chemother. 62, e01179-17 (2018). source
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In the paper
“most commonly involving disomy of chromosome 1, which contains ERG11 and the predominant efflux pump gene AFR1 (ref.17).”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [17] Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 6, e1000848 (2010). source
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In the paper
“This phenomenon was first described in 1999, when researchers observed that a subset of Cryptococcus cells were able to grow at azole concentrations well above the inhibitory concentration in vitro21.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [21] Mondon, P. et al. Heteroresistance to fluconazole and voriconazole in Cryptococcus neoformans. Antimicrob. Agents Chemother. 43, 1856–1861 (1999). source
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In the paper
“However, hypermutator phenotypes can also result from mutations in other genes, such as MSL1 and PMS1 (ref.30).”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [30] Boyce, K. J. et al. Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans. mBio 8, e00595-17 (2017). This report is one of the first of a hypermutator strain in clinical isolates, which has a fitness advantage owing to mutations in mismatch repair genes. source
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In the paper
“Disomy of chromosome 4 is the second most common aneuploidy conferring azole heteroresistance, which is largely attributed to three genes: SEY1, which encodes a GTPase, and GLO3 and GCS2, which encode ADP-ribosylation factor proteins25.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [25] Ngamskulrungroj, P. et al. Characterization of the chromosome 4 genes that affect fluconazole-induced disomy formation in Cryptococcus neoformans. PLoS ONE 7, e33022 (2012).
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In the paper
“Heteroresistance primarily occurs through the formation of aneuploid cells, both in vitro and in vivo17,22,24 (Fig. 1)”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [17] Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 6, e1000848 (2010). source
- Not checked yetcites [22] Stone, N. R. et al. Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis. J. Clin. Invest. 129, 999–1014 (2019). This paper presents the first clinical samples to demonstrate fluconazole heteroresistance due to aneuploidy, achieved through increased efflux levels. source
- Not checked yetcites [24] Sionov, E., Chang, Y. C. & Kwon-Chung, K. J. Azole heteroresistance in Cryptococcus neoformans: emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment. Antimicrob. Agents Chemother. 57, 5127–5130 (2013). source
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In the paper
“a phase II trial demonstrated that a single high dose of LAmB is of equivalent efficacy to a 7-day course of DAmB10”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [10] Jarvis, J. N. et al. Short-course high-dose liposomal amphotericin B for human immunodeficiency virus-associated cryptococcal meningitis: a phase 2 randomized controlled trial. Clin. Infect. Dis. 68, 393–401 (2019). source
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In the paper
“Furthermore, these transposable elements also mediated resistance to rapamycin, FK506 and flucytosine38.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [38] Gusa, A. et al. Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro. Proc. Natl Acad. Sci. USA 117, 9973–9980 (2020). This paper is the first description of transposon-mediated antifungal resistance in Cryptococcus spp. source
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In the paper
“Aneuploidy has been reported for other chromosomes, including chromosomes 6, 10, 11 and 14, although the specific genetic elements responsible for the selective advantage remain unclear17,22,25,26.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [17] Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 6, e1000848 (2010). source
- Not checked yetcites [22] Stone, N. R. et al. Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis. J. Clin. Invest. 129, 999–1014 (2019). This paper presents the first clinical samples to demonstrate fluconazole heteroresistance due to aneuploidy, achieved through increased efflux levels. source
- Not checked yetcites [25] Ngamskulrungroj, P. et al. Characterization of the chromosome 4 genes that affect fluconazole-induced disomy formation in Cryptococcus neoformans. PLoS ONE 7, e33022 (2012).
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“A new form of encochleated oral amphotericin B (CAmB), where amphotericin B is encapsulated in a lipid-containing crystal nanoparticle, is effectively delivered to the central nervous system and displays antifungal efficacy in a mouse model11.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [11] Lu, R. et al. Efficacy of oral encochleated amphotericin B in a mouse model of cryptococcal meningoencephalitis. mBio 10, e00724-19 (2019).
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In the paper
“The phase III trial reported 10-week mortality of 24%, which is a considerable improvement compared with the current ~70% mortality rate in many low- and middle-income countries in Africa6,14.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [6] Rajasingham, R. et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect. Dis. 17, 873–881 (2017). source
- Not checked yetcites [14] Molloy, S. F. et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N. Engl. J. Med. 378, 1004–1017 (2018). This seminal study provides guidelines adopted by the WHO for combatting cryptococcal infections. source
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In the paper
“a clinical trial with patients who are HIV-positive and suffering from cryptococcal meningitis showed that the combination of amphotericin B with the fluorinated pyrimidine analogue flucytosine, followed by the triazole fluconazole, improved survival rates compared with amphotericin B alone and minimized toxic effects13.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [13] Day, J. N. et al. Combination antifungal therapy for cryptococcal meningitis. N. Engl. J. Med. 368, 1291–1302 (2013). This important clinical trial shows that the combination of amphotericin B and flucytosine improves survival of patients with cryptococcal meningitis. source
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In the paper
“An estimated 223,100 cases of cryptococcal meningitis occur globally each year, leading to 181,100 deaths6.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Introduction
What the sources say
- Not checked yetcites [6] Rajasingham, R. et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect. Dis. 17, 873–881 (2017). source
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In the paper
“These mutations result in an ~200-fold higher mutation rate than in standard laboratory strains30 and preferentially affect genes containing homopolymer runs33.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [30] Boyce, K. J. et al. Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans. mBio 8, e00595-17 (2017). This report is one of the first of a hypermutator strain in clinical isolates, which has a fitness advantage owing to mutations in mismatch repair genes. source
- Not checked yetcites [33] Billmyre, R. B., Clancey, S. A. & Heitman, J. Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii. eLife 6, e28802 (2017). source
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In the paper
“This increase in chitin induces a T helper 2-type allergic response and cytokine release, rather than a protective T helper 1-type response, which leads to increased mortality in infected mice152.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Morphological alterations
What the sources say
- Not checked yetcites [152] Wiesner, D. L. et al. Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection. PLoS Pathog. 11, e1004701 (2015). source
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In the paper
“C. neoformans cells with thicker capsules exhibit amphotericin B resistance and enhanced virulence40,41”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Morphological alterations
What the sources say
- Not checked yetcites [40] Cordoba, S., Afeltra, J. & Vitale, R. G. Evaluation of the in vitro activity of amphotericin B by time-kill curve methodology against large and small capsulate C. neoformans isolates. Diagn. Microbiol. Infect. Dis. 71, 260–262 (2011). source
- Not checked yetcites [41] Park, Y. D. et al. A role for LHC1 in higher order structure and complement binding of the Cryptococcus neoformans capsule. PLoS Pathog. 10, e1004037 (2014).
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A genetic screen of more than 10,000 C. neoformans mutants provided insight into this inherent resistance46. This screen identified CDC50 (encoding the β-subunit of a lipid flippase enzyme) as integral to echinocandin resistance and further demonstrated its involvement in maintaining lipid asymmetry of the phospholipid membrane46.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Intrinsic resistance to echinocandins
What the sources say
- Not checked yetcites [46] Huang, W. et al. Lipid flippase subunit Cdc50 mediates drug resistance and virulence in Cryptococcus neoformans. mBio 7, e00478-16 (2016). This paper provides foundational genetic insights into the intrinsic echinocandin resistance of Cryptococcus. source
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In the paper
“This transition can be triggered by the bacterial peptidoglycan subunit muramyl dipeptide in serum and is regulated by USV101 (ref.149) as well as STE3a and GPR5 (ref.150), which converge on the cAMP–PKA pathway149,150.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Morphological alterations
What the sources say
- Not checked yetcites [149] Dambuza, I. M. et al. The Cryptococcus neoformans titan cell is an inducible and regulated morphotype underlying pathogenesis. PLoS Pathog. 14, e1006978 (2018). source
- Not checked yetcites [150] Okagaki, L. H. et al. Cryptococcal titan cell formation is regulated by G-protein signaling in response to multiple stimuli. Eukaryot. Cell 10, 1306–1316 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“On titan cell formation, the polysaccharide capsule surrounding Cryptococcus cells becomes condensed and highly crosslinked151; the cell wall can increase in thickness from 50–100 nm to 2–3 µm (ref.147), and the cell wall composition is altered through an increase in chitin content and a decrease in glucan152.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Morphological alterations
What the sources say
- Not checked yetcites [147] Zaragoza, O. et al. Fungal cell gigantism during mammalian infection. PLoS Pathog. 6, e1000945 (2010). source
- Not checked yetcites [151] Mukaremera, L. et al. Titan cell production in Cryptococcus neoformans reshapes the cell wall and capsule composition during infection. Cell Surf. 1, 15–24 (2018). source
- Not checked yetcites [152] Wiesner, D. L. et al. Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection. PLoS Pathog. 11, e1004701 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Cdc50 directly interacts with Crm1 and negatively regulates its expression47.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Intrinsic resistance to echinocandins
What the sources say
- Not checked yetcites [47] Cao, C., Wang, Y., Husain, S., Soteropoulos, P. & Xue, C. A mechanosensitive channel governs lipid flippase-mediated echinocandin resistance in Cryptococcus neoformans. mBio 10, e01952-19 (2019).
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In the paper
“Despite these alarming statistics, treatment options for cryptococcosis remain limited, with only three major classes of drugs approved for clinical use.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Abstract
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In the paper
“These traits can be inherited, and are often transient, such that they are lost when the stress is removed17,18.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms
What the sources say
- Not checked yetcites [17] Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 6, e1000848 (2010). source
- Not checked yetcites [18] Sionov, E., Chang, Y. C., Garraffo, H. M. & Kwon-Chung, K. J. Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob. Agents Chemother. 53, 2804–2815 (2009). source
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In the paper
“Scarcity of these two drugs has resulted in the widespread use of the much less effective fluconazole monotherapy, which explains the dramatically high mortality rate in these low- and middle-income African countries4,7.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [4] Perfect, J. R. et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 291–322 (2010). source
- Not checked yetcites [7] Loyse, A. et al. Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries. Lancet Infect. Dis. 19, e143–e147 (2019). source
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In the paper
“immunocompromised individuals are most vulnerable, but there are also reports of cryptococcal infections in immunocompetent hosts4,5”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Introduction
What the sources say
- Not checked yetcites [4] Perfect, J. R. et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 291–322 (2010). source
- Not checked yetcites [5] Kwon-Chung, K. J. et al. Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis. Cold Spring Harb. Perspect. Med. 4, a019760 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment options for invasive cryptococcal infection are limited, given that Cryptococcus spp. are intrinsically resistant to echinocandins and that they employ an arsenal of defences that enable resistance to azoles2,8.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [2] Lee, Y., Puumala, E., Robbins, N. & Cowen, L. E. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem. Rev. https://doi.org/10.1021/acs.chemrev.0c00199 (2020). source
- Not checked yetcites [8] Denning, D. W. Echinocandin antifungal drugs. Lancet 362, 1142–1151 (2003). source
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In the paper
“In low- and middle-income countries, flucytosine is not available owing to market failure and lack of in-country registration, whereas access to amphotericin B and its liposomal form is limited due to the high cost and lack of safe intravenous administration7.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [7] Loyse, A. et al. Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries. Lancet Infect. Dis. 19, e143–e147 (2019). source
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In the paper
“C. neoformans and Cryptoccocus gattii are the major species responsible for life-threatening cryptococcal meningitis”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Introduction
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In the paper
“Heteroresistance has major clinical implications, as the proportion of resistant cells increases over the course of therapy, making this mechanism a major contributor to relapse during azole maintenance therapy22,23.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [22] Stone, N. R. et al. Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis. J. Clin. Invest. 129, 999–1014 (2019). This paper presents the first clinical samples to demonstrate fluconazole heteroresistance due to aneuploidy, achieved through increased efflux levels. source
- Not checked yetcites [23] Rhodes, J. et al. A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection. G3 7, 1165–1176 (2017). source
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In the paper
“the polyene amphotericin B has been the primary treatment for cryptococcal infection for more than half a century, despite the fact that it causes substantial toxicity and that its availability is limited by economic and logistical constraints2,4”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Treatments for cryptococcal infections
What the sources say
- Not checked yetcites [2] Lee, Y., Puumala, E., Robbins, N. & Cowen, L. E. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem. Rev. https://doi.org/10.1021/acs.chemrev.0c00199 (2020). source
- Not checked yetcites [4] Perfect, J. R. et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 291–322 (2010). source
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In the paper
“The Cryptococcus polysaccharide capsule modulates immune responses, enhances pathogenicity and confers protection against oxidative stress55,56.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
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In the paper
“this rapid genome alteration resulting in aneuploid cells has been proposed as an alternative mechanism of heteroresistance43.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Morphological alterations
What the sources say
- Not checked yetcites [43] Zafar, H., Altamirano, S., Ballou, E. R. & Nielsen, K. A titanic drug resistance threat in Cryptococcus neoformans. Curr. Opin. Microbiol. 52, 158–164 (2019). This seminal review summarizes the current understanding of the mechanisms underlying antifungal resistance of the Cryptococcus titan cell. source
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In the paper
“transposon-driven mutagenesis was enhanced in multiple strains at 37 °C compared with that at 30 °C, suggesting that the body temperature of a mammalian host may amplify this phenomenon38.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Antifungal resistance mechanisms > Genomic plasticity
What the sources say
- Not checked yetcites [38] Gusa, A. et al. Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro. Proc. Natl Acad. Sci. USA 117, 9973–9980 (2020). This paper is the first description of transposon-mediated antifungal resistance in Cryptococcus spp. source
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In the paper
“enabling the design of APX879, an FK506 analogue with an acetohydrazine substitution of the C22 carbonyl, which has 70-fold lower immunosuppressive effects than FK506 while retaining antifungal activity77”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Stress responses
What the sources say
- Not checked yetcites [77] Juvvadi, P. R. et al. Harnessing calcineurin–FK506–FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat. Commun. 10, 4275 (2019). This paper presents an excellent example of successful structure-guided drug design to develop fungal-specific calcineurin inhibitors. source
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In the paper
“Melanin is produced by laccases, which are upregulated in C. neoformans clinical and environmental isolates66”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [66] Lahiri, S. et al. In vitro expression of vital virulent genes of clinical and environmental isolates of Cryptococcus neoformans/gattii in endothelial cells of human blood–brain barrier. J. Mycol. Med. 29, 239–244 (2019). source
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In the paper
“The fungal cell wall is a dynamic structure that is important not only for cell integrity but also for modulating the host immune response39.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [39] Garcia-Rubio, R., de Oliveira, H. C., Rivera, J. & Trevijano-Contador, N. The fungal cell wall: Candida, Cryptococcus, and Aspergillus species. Front. Microbiol. 10, 2993 (2019). source
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In the paper
“Deletion of the gene encoding either of these enzymes impairs capsule linkage and reduces the fungal burden in infections in mice41,57.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [41] Park, Y. D. et al. A role for LHC1 in higher order structure and complement binding of the Cryptococcus neoformans capsule. PLoS Pathog. 10, e1004037 (2014).
- Not checked yetcites [57] Klutts, J. S. & Doering, T. L. Cryptococcal xylosyltransferase 1 (Cxt1p) from Cryptococcus neoformans plays a direct role in the synthesis of capsule polysaccharides. J. Biol. Chem. 283, 14327–14334 (2008). source
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In the paper
“For example, phospholipase B1 (encoded by PLB1) facilitates Cryptococcus adherence to and invasion of the host cell, contributes to fungal cell wall integrity and degrades host cell membranes, thereby providing nutrients that support fungal survival69,70.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [69] Wright, L. C. et al. Cryptococcal lipid metabolism: phospholipase B1 is implicated in transcellular metabolism of macrophage-derived lipids. Eukaryot. Cell 6, 37–47 (2007). source
- Not checked yetcites [70] Siafakas, A. R. et al. Cell wall-linked cryptococcal phospholipase B1 is a source of secreted enzyme and a determinant of cell wall integrity. J. Biol. Chem. 282, 37508–37514 (2007). source
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In the paper
“The C. neoformans homologue of mTOR kinase, Tor1, is essential for Cryptococcus stress response signalling, virulence84,85 and fluconazole tolerance (that is, the ability of a drug-susceptible organism to grow in the presence of an antifungal drug at concentrations above the minimum inhibitory concentration)86.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Stress responses
What the sources say
- Not checked yetcites [84] Lee, H., Khanal Lamichhane, A., Garraffo, H. M., Kwon-Chung, K. J. & Chang, Y. C. Involvement of PDK1, PKC and TOR signalling pathways in basal fluconazole tolerance in Cryptococcus neoformans. Mol. Microbiol. 84, 130–146 (2012). source
- Not checked yetcites [85] So, Y. S., Lee, D. G., Idnurm, A., Ianiri, G. & Bahn, Y. S. The TOR pathway pays pleiotropic roles in growth and stress responses of the fungal pathogen Cryptococcus neoformans. Genetics 212, 1241–1258 (2019). source
- Not checked yetcites [86] Berman, J. & Krysan, D. J. Drug resistance and tolerance in fungi. Nat. Rev. Microbiol. 18, 319–331 (2020). source
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In the paper
“An inhibitor of Hsp90 with 25-fold greater selectivity for Candida albicans Hsp90 than for human HSP90 (ref.81) and aminopyrazole-substituted resorcylate amides with more than 30-fold greater selectivity for C. neoformans Hsp90 than for human HSP90 (ref.82) have been identified”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Stress responses
What the sources say
- Not checked yetcites ref.81
- Not checked yetcites ref.82
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Finally, the secreted peptide Qsp1 is an important virulence determinant that acts as an autoregulatory signalling molecule and is transported into the fungal cell through Opt1 to initiate a diverse transcriptional response, including the production of proteases and activation of cell wall integrity72,73.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [72] Lee, H., Chang, Y. C., Nardone, G. & Kwon-Chung, K. J. TUP1 disruption in Cryptococcus neoformans uncovers a peptide-mediated density-dependent growth phenomenon that mimics quorum sensing. Mol. Microbiol. 64, 591–601 (2007). source
- Not checked yetcites [73] Homer, C. M. et al. Intracellular action of a secreted peptide required for fungal virulence. Cell Host Microbe 19, 849–864 (2016). source
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In the paper
“In particular, melanin is a major virulence factor that protects fungal cells from oxidative damage, antifungal assault and high temperature, and also modulates host immune responses39.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [39] Garcia-Rubio, R., de Oliveira, H. C., Rivera, J. & Trevijano-Contador, N. The fungal cell wall: Candida, Cryptococcus, and Aspergillus species. Front. Microbiol. 10, 2993 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hsp90 inhibition has been shown to impair C. neoformans virulence traits, such as capsule assembly, and increase susceptibility to antifungal agents79,80.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Stress responses
What the sources say
- Not checked yetcites [79] Chatterjee, S. & Tatu, U. Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans. PLoS Negl. Trop. Dis. 11, e0005836 (2017). source
- Not checked yetcites [80] Cordeiro, R. A. et al. Inhibition of heat-shock protein 90 enhances the susceptibility to antifungals and reduces the virulence of Cryptococcus neoformans/Cryptococcus gattii species complex. Microbiology 162, 309–317 (2016). source
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In the paper
“Deletion of CAP10, CAP60 and PXB1 not only blocks capsule production but also leads to attenuated virulence52,58.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Potential therapeutic targets > Virulence factors
What the sources say
- Not checked yetcites [52] Liu, O. W. et al. Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell 135, 174–188 (2008). source
- Not checked yetcites [58] Almeida, F., Wolf, J. M. & Casadevall, A. Virulence-associated enzymes of Cryptococcus neoformans. Eukaryot. Cell 14, 1173–1185 (2015). source
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In the paper
“but mefloquine derivatives have been identified that have improved in vitro antifungal activity and that impede C. neoformans capsule formation and melanization104.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [104] Montoya, M. C., Beattie, S., Alden, K. M. & Krysan, D. J. Derivatives of the antimalarial drug mefloquine are broad-spectrum antifungal molecules with activity against drug-resistant clinical isolates. Antimicrob. Agents Chemother. 64, e02331-19 (2020). source
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In the paper
“Another example is the macrolides, commonly used antibiotics that target protein synthesis, which reduce capsule formation in C. gattii, impairing this key virulence trait and resulting in enhanced phagocytosis and inflammatory cytokine production by macrophages in culture59.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [59] Nakamura, S. et al. Macrolides inhibit capsule formation of highly virulent Cryptococcus gattii and promote innate immune susceptibility. Antimicrob. Agents Chemother. 63, e02364-18 (2019).
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In the paper
“Clinical trials with APX001 for the treatment of cryptococcosis are starting imminently, and phase II trials for the treatment of invasive infections caused by Aspergillus spp. and Candida spp. are currently underway (NCT02957929, NCT02956499 and NCT04240886)”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Promising chemical matter
What the sources say
- Not checked yetcites NCT02957929
- Not checked yetcites NCT02956499
- Not checked yetcites NCT04240886
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In the paper
“Gwt1, an important virulence factor and the enzyme responsible for catalysing an early step in glycosylphosphatidylinositol (GPI)-anchor biosynthesis96, has also emerged as a promising antifungal target.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Promising chemical matter
What the sources say
- Not checked yetcites [96] Zhao, Q. et al. GWT1 encoding an inositol acyltransferase homolog is required for laccase repression and stress resistance in the basidiomycete Cryptococcus neoformans. FEMS Yeast Res. 15, fov086 (2015). source
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In the paper
“Similarly, tamoxifen, an oestrogen receptor modulator that is used to treat and prevent breast cancer and osteoporosis, also displayed potent anti-cryptococcal activity in vitro106 and in a mouse model of disseminated cryptococcosis107.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [106] Dolan, K. et al. Antifungal activity of tamoxifen: in vitro and in vivo activities and mechanistic characterization. Antimicrob. Agents Chemother. 53, 3337–3346 (2009). source
- Not checked yetcites [107] Butts, A. et al. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio 5, e00765-13 (2014). source
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In the paper
“Of these 31 molecules, the largest class of inhibitors identified were antipsychotic agents, with general antiseptic agents following close behind111.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [111] Butts, A. et al. A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis. Eukaryot. Cell 12, 278–287 (2013). source
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In the paper
“Similar to other clinically approved azoles, VT-1598 displays broad-spectrum activity against diverse fungi, including a strong therapeutic potential in a mouse model of cryptococcal meningitis101.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Promising chemical matter
What the sources say
- Not checked yetcites [101] Garvey, E. P., Sharp, A. D., Warn, P. A., Yates, C. M. & Schotzinger, R. J. The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis. J. Antimicrob. Chemother. 73, 2815–2822 (2018). source
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In the paper
“Fenbendazole displays potent in vitro activity against C. neoformans and C. gattii, as well as in vivo activity in a mouse model of cryptococcosis103.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [103] de Oliveira, H. C. et al. Fenbendazole controls in vitro growth, virulence potential, and animal infection in the Cryptococcus model. Antimicrob. Agents Chemother. 64, e00286-20 (2020). source
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In the paper
“A high-throughput screen of >300,000 compounds from the US National Institutes of Health (NIH) Molecular Libraries Program was undertaken to identify agents with fungicidal activity against C. neoformans, where secondary assays prioritized compounds that interfered with fungal cell wall integrity91.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Promising chemical matter
What the sources say
- Not checked yetcites [91] Hartland, K. et al. High-throughput screen in Cryptococcus neoformans identifies a novel molecular scaffold that inhibits cell wall integrity pathway signaling. ACS Infect. Dis. 2, 93–102 (2016). source
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In the paper
“Systematic analysis of these apparently inactive compounds revealed that they are not biologically inert, and even identified a potent inhibitor of C. neoformans growth in vitro87.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Promising chemical matter
What the sources say
- Not checked yetcites [87] Wassermann, A. M. et al. Dark chemical matter as a promising starting point for drug lead discovery. Nat. Chem. Biol. 11, 958–966 (2015). This paper reaffirms that dark chemical matter compounds can be attractive lead compounds and demonstrates the potential for anti-cryptococcal drug discovery. source
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- Rests on an assumption: Most compound libraries have been designed to maximize drug-like properties with respect to mammalian targets and physiology, whereas antifungal drugs require unique physicochemical properties.
In the paper
“The efficacy of fenbendazole was attributed to its growth-inhibitory properties, its inhibition of Cryptococcus virulence determinants and its inhibition of fungal proliferation inside macrophages103.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [103] de Oliveira, H. C. et al. Fenbendazole controls in vitro growth, virulence potential, and animal infection in the Cryptococcus model. Antimicrob. Agents Chemother. 64, e00286-20 (2020). source
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In the paper
“Combination therapy has the potential to confer enhanced efficacy and fungal selectivity while reducing vulnerability to the evolution of resistance2.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Drug combination therapy
What the sources say
- Not checked yetcites [2] Lee, Y., Puumala, E., Robbins, N. & Cowen, L. E. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem. Rev. https://doi.org/10.1021/acs.chemrev.0c00199 (2020). source
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In the paper
“The amphipathic nature of this motif permits the crossing of biological membranes, a property that is important for traversing the blood–brain barrier and accessing cryptococcal cells that reside within the lysosome or phagolysosome of host cells114.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Repurposing old drugs
What the sources say
- Not checked yetcites [114] Banks, W. A. Characteristics of compounds that cross the blood–brain barrier. BMC Neurol. 9, S3 (2009). source
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In the paper
“Heat-killed mutant strains have also been reported to induce strong T helper 1 cell responses, resulting in full protection against C. neoformans challenge65,136.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Immunotherapy and vaccine development
What the sources say
- Not checked yetcites [65] Upadhya, R. et al. Induction of protective immunity to cryptococcal infection in mice by a heat-killed, chitosan-deficient strain of Cryptococcus neoformans. mBio 7, e00547-16 (2016). source
- Not checked yetcites [136] Zhai, B. et al. Development of protective inflammation and cell-mediated immunity against Cryptococcus neoformans after exposure to hyphal mutants. mBio 6, e01433-15 (2015). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Specifically, mice vaccinated with glucan particles containing cryptococcal antigens mounted antigen-specific T cell responses and sustained protection against cryptococcosis138.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Immunotherapy and vaccine development
What the sources say
- Not checked yetcites [138] Specht, C. A. et al. Vaccination withrecombinant Cryptococcus proteins in glucan particles protects mice against cryptococcosis in a manner dependent upon mouse atrain and cryptococcal species. mBio 8, e01872-17 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Similar protective effects were seen with an avirulent but live mutant strain of C. neoformans lacking sterylglucosidase (sglΔ)134,135.”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Immunotherapy and vaccine development
What the sources say
- Not checked yetcites [134] Wormley, F. L. Jr., Perfect, J. R., Steele, C. & Cox, G. M. Protection against cryptococcosis by using a murine γ interferon-producing Cryptococcus neoformans strain. Infect. Immun. 75, 1453–1462 (2007). source
- Not checked yetcites [135] Rella, A. et al. Role of sterylglucosidase 1 (Sgl1) on the pathogenicity of Cryptococcus neoformans: potential applications for vaccine development. Front. Microbiol. 6, 836 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
The paper relies on this without support.
Virulence factors are not required for the growth of the pathogen but are crucial for causing disease.
“Targeting virulence factors, which are not required for the growth of the pathogen but, instead, are crucial for causing disease, opens up a plethora of new targets for drug development.”
The paper relies on this without support.
The fungal cell wall is absent from mammalian cells.
“This structure is absent from mammalian cells, and therefore great efforts have been made to develop antifungal agents that target this unique structure directly or that impair its biosynthesis.”
The paper relies on this without support.
Most compound libraries have been designed to maximize drug-like properties with respect to mammalian targets and physiology, whereas antifungal drugs require unique physicochemical properties.
“The development of new antifungal molecules remains a considerable challenge, as most compound libraries have been designed to maximize their ‘drug-like’ properties with respect to mammalian targets and physiology, whereas antifungal drugs require unique physicochemical properties, owing in part to the need for these molecules to transverse the fungal cell wall.”
The paper relies on this without support.
Antifungal molecules need good central nervous system penetration and should be able to be administered orally to ensure widespread access within developing countries with limited resources.
“Furthermore, because of the unique neurological features of cryptococcal disease, antifungal molecules are needed that have good central nervous system penetration, and they should be able to be administered orally to ensure widespread access within developing countries with limited resources.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“C. neoformans is intrinsically resistant to echinocandins, and therefore treatment options remain limited to polyenes, azoles, and the pyrimidine analog flucytosine that targets RNA and DNA synthesis (Denning 2003; Iyer et al. 2021).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Iyer et al. 2021
In the citing paper
“C. neoformans is also able to develop resistance to all other current antifungals by employing a plethora of genetic, genomic, and adaptive biological strategies (Iyer et al. 2021).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Iyer et al. 2021
In the citing paper
“Essential genes that are required for survival serve as optimal targets for novel antifungal development (Iyer et al. 2021).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Iyer et al. 2021
In the citing paper
“only a small number of essential genes have been identified and characterized in C. neoformans due to the technical challenges of genetic manipulation in this organism (Ianiri and Idnurm 2015; Iyer et al. 2021).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Iyer et al. 2021
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Introduction
“| Monoclonal antibody 18B7 | Binds to the capsular component glucuronoxylomannan | Efficacy displayed in basic research |”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Immunotherapy and vaccine development
“With promising anti-cryptococcal effects in rodent models, 18B7 was evaluated in a phase I/II trial in patients with AIDS-related cryptococcal meningitis132.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Introduction
“C. neoformans var. neoformans (serotype D) and C. neoformans var. grubii (serotype A)”
§ Treatment strategies for cryptococcal infection: challenges, advances and future outlook > Introduction
“serotype A isolates comprising var. neoformans (VN) lineages VNI and VNII”
Citations
Cites
Hidden Killers: Human Fungal Infections
Brown, G. D., Denning, D. W., Gow, N. A. R., Levitz, S. M., Netea, M. G., & White, T. C. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004404 · Cited by 4,284
Perfect, J. R., Dismukes, W. E., Dromer, F., Goldman, D. L., Graybill, J. R., Hamill, R. J., Harrison, T. S., Larsen, R. A., Lortholary, O., Nguyen, M.-H., et al. (2010) · Clinical Infectious Diseases · doi:10.1086/649858 · Cited by 2,660
Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis
Rajasingham, R., Smith, R. M., Park, B. J., Jarvis, J. N., Govender, N. P., Chiller, T. M., Denning, D. W., Loyse, A., & Boulware, D. R. (2017) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(17)30243-8 · Cited by 1,861
Worldwide emergence of resistance to antifungal drugs challenges human health and food security
Fisher, M. C., Hawkins, N. J., Sanglard, D., & Gurr, S. J. (2018) · Science · doi:10.1126/science.aap7999 · Cited by 1,555
Denning, D. W. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14472-8 · Cited by 1,131
The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species
Garcia-Rubio, R., de Oliveira, H. C., Rivera, J., & Trevijano-Contador, N. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02993 · Cited by 917
Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond
Lee, Y., Puumala, E., Robbins, N., & Cowen, L. E. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00199 · Cited by 801
Self-citationRecognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex
Hagen, F., Khayhan, K., Theelen, B., Kolecka, A., Polacheck, I., Sionov, E., Falk, R., Parnmen, S., Lumbsch, H. T., & Boekhout, T. (2015) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2015.02.009 · Cited by 723
Characteristics of Compounds that Cross the Blood-Brain Barrier
Banks, W. A. (2009) · BMC Neurology · doi:10.1186/1471-2377-9-s1-s3 · Cited by 710
Drug resistance and tolerance in fungi.
Berman, J., & Krysan, D. J. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0322-2 · Cited by 642
Research works printed but not linked: 1
- Chen, Y. et al. Microevolution of serial clinical isolates of Cryptococcus neoformans var. grubii and C. gattii. mBio 8, e00166-17 (2017).
Cited by
Sorted by citations
Ali, A., Shah, T., Ullah, R., Zhou, P., Guo, M., Ovais, M., Tan, Z., & Rui, Y. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.629054 · Cited by 650
Molecular mechanisms governing antifungal drug resistance
Lee, Y., Robbins, N., & Cowen, L. E. (2023) · npj Antimicrobials and Resistance · doi:10.1038/s44259-023-00007-2 · Cited by 304
Self-citationFungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond
Bastos, R. W., Rossato, L. L., Goldman, G. H., & Santos, D. A. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1010073 · Cited by 120
Advancements and challenges in antifungal therapeutic development
Puumala, E., Fallah, S., Robbins, N., & Cowen, L. E. (2024) · Clinical Microbiology Reviews · doi:10.1128/cmr.00142-23 · Cited by 128
Self-citationAntifungals: From Pharmacokinetics to Clinical Practice
do Carmo, A., Rocha, M. J., Pereirinha, P., Tomé, R., & Costa, E. (2023) · Antibiotics · doi:10.3390/antibiotics12050884 · Cited by 115
Metadata
- Authors
- Iyer, K. R., Revie, N. M., Fu, C., Robbins, N., & Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Cowen, Leah E.
- Venue
- Nature Reviews Microbiology
- Published
- 2021-02-08
- Volume
- 19
- Issue
- 7
- Pages
- 454-466
- ISSN
- 1740-1526 (ISSN-L)
- 1740-1534
- PMC
- PMC7868659
- OpenAlex
- W3127236674
- Semantic Scholar
- b3debc518effc79a3f7043a7e5e11118b45e854d
- Cited by
- 363
- References
- 161
- Citations by year
- 2026: 50 · 2025: 84 · 2024: 82 · 2023: 55 · 2022: 55 · 2021: 35
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Microbiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institute for Advanced Research
- National Institutes of Health (NIAID R21)
- Canadian Institutes of Health Research (FDN154288)
- National Institute of Allergy and Infectious Diseases (R01AI127375, R21AI141080, R01AI120958)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Keywords
- cryptococcosis, cryptococcal meningitis, Cryptococcus neoformans, Cryptococcus gattii, antifungal resistance, echinocandins, combination therapy, stress response pathways, antifungal drug discovery, host-pathogen interaction
- MeSH terms
- Antifungal Agents, Cell Wall, Cryptococcosis, Cryptococcus, Drug Resistance, Fungal, Virulence Factors, Echinocandins, Fungal Capsules, Fungal Polysaccharides
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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