A titanic drug resistance threat in Cryptococcus neoformans

Zafar, Hanna; Altamirano, Sophie; Ballou, Elizabeth R.; Nielsen, Kirsten

doi:10.1016/j.mib.2019.11.001

Cited by 56 publications

(58 citation statements)

References 77 publications

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“…Aneuploidy is associated with increased resistance to fluconazole, which continues to be used as a frontline antifungal in resource limited settings. Fluconazole resistance in C. neoformans is linked to aneuploidy of chromosomes 1, 4, 6, and 10 due to the presence of genes on these chromosomes that directly enable fluconazole resistance, however the contribution of titanization to resistance remains unclear (37). We therefore assessed the impact of altered ploidy on drug resistance of individual colonies isolated from the lungs and brains of infected mice (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Gerstein et al previously demonstrated that in vivo- derived titans provide daughters with a survival advantage compared to in vivo- derived typical cells. Titan-derived colonies are resistant to fluconazole via aneuploidy of chromosomes 1, 4, 10, 11, and/or 12 when propagated in the presence of fluconazole, suggesting that titanization drives fluconazole resistance in vivo (11, 37). Our data support these findings, with overall increases in population diversity in titanizing strains compared to non-titanizing strains following passage through mice (Figure 3A).…”

Section: Discussionmentioning

confidence: 99%

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Host environmental conditions induce small fungal cell size and alter population heterogeneity in Cryptococcus neoformans

Zhou

Zafar

Sephton-Clark

et al. 2020

Preprint

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Fungal morphology significantly impacts the host response. Filamentation and tissue penetration by Candida and Aspergillus species are essential for virulence, while growth as a yeast allows the thermal dimorphic fungi Coccidiodes, Histoplasma, and Talaromyces to reside inside phagocytes and disseminate. The basidiomycete Cryptococcus neoformans exhibits an unusual yeast-to-titan transition thought to enhance pathogenicity by increasing fungal survival in the host lung and dissemination to the central nervous system. In a common laboratory strain (H99), in vitro and in vivo titan induction yields a heterogenous population including >10 μm titan cells, 5-7 μm yeast cells and 2-4 μm titanides. Previous reports have shown that titan cells are associated with enhanced virulence and the generation of aneuploid cells that facilitate stress adaptation and drug resistance, while small (>10 μm) cells are associated with increased dissemination. However, the relationship between titan cells, small cells, and titanides remains unclear. Here, we characterize titanides and small cells in H99 and three clinical isolates and show that titanides share the lipid membrane order of their titan mothers and the G0 quiescent-like DNA staining of mating spores. In addition, we show that both titanizing and non-titanizing isolates exhibit altered capsule structure and PAMP exposure over time during in vitro culture, and generate aneuploidy in vivo.Author summaryThe human fungal pathogen Cryptococcus neoformans causes 200,000 HIV-associated deaths each year. In the lung, Cryptococcus makes an unusual yeast-to-titan morphological switch that contributes to disease development by altering immune polarization and introducing aneuploidy underlying host stress and drug resistance. Specifically, a proportion of 5 um haploid yeast endoreduplicate and swell, converting to large (> 10 um) polyploid titan cells that can then produce genetically distinct daughter cells. We recently developed an in vitro protocol for inducing large titan cells and additionally observed a novel small “titanide” cell type. Here we investigate the nature and origin of these small cells, demonstrating that they emerge during both in vitro and in vivo mouse-passaged titan induction in the well characterised lab strain H99 and are also apparent in a titanizing clinical isolate, Zc8. We show that these titanide cells share features with titan mothers (lipid order) and with spores produced during heterothalic mating. Finally, we show that the capacity of clinical isolates to produce both titan and titanide cells impacts aneuploidy and the emergence of drug resistance in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Host environmental conditions induce small fungal cell size and alter population heterogeneity in Cryptococcus neoformans

Zhou

Zafar

Sephton-Clark

et al. 2020

Preprint

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“…For example, C. neoformans cells with thicker capsules exhibit amphotericin B resistance and enhanced virulence 40 , 41 , and the thicker cell walls of older C. neoformans cells have been implicated in their increased antifungal resistance 42 . Finally, the ability of fungi to undergo dramatic morphological transitions is exemplified by the formation of Cryptococcus titan cells, which exhibit numerous alterations that likely contribute to drug resistance 43 (Box 2 ).…”

Section: Antifungal Resistance Mechanismsmentioning

confidence: 99%

“…Although titan daughter cells can be haploid, under fluconazole-induced stress conditions they are more often aneuploid, specifically with a disomy of chromosomes 1 or 4, which results in improved growth in the presence of fluconazole 26 . Furthermore, this rapid genome alteration resulting in aneuploid cells has been proposed as an alternative mechanism of heteroresistance 43 . Enigmatically, titan cell populations also have an increased growth advantage compared with typical haploid cells on exposure to oxidative and nitrosative stress, which is not mediated through aneuploid formation 26 , suggesting that titan cells have additional unknown mechanisms of propagating stress resistance to their progeny.…”

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confidence: 99%

Treatment strategies for cryptococcal infection: challenges, advances and future outlook

et al. 2021

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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.

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“…The two papers are distinct in their approaches, and their findings reinforce rather than directly replicate each other, enabling increased confidence in the importance of the phenotype to C. neoformans pathogenesis from the wider community. This approach also ensured that both Nielsen and Zaragoza could go on to publish important subsequent work which has been the foundation of a whole field of research with implications for patient outcomes (8,9).…”

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confidence: 99%

mSphere of Influence: Positive Research Culture Enables Excellence and Innovation

Ballou

2020

mSphere

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Elizabeth Ballou works in the field of medical mycology. In this mSphere of Influence article, she reflects on how two papers by Okagaki et al. (PLoS Pathog 6:e1000953, 2010, https://doi.org/10.1371/journal.ppat.1000953) and Zaragoza et al. (PLoS Pathog 6:e1000945, 2010, https://doi.org/10.1371/journal.ppat.1000945) made an impact on her career by demonstrating an alternative to destructive publication practices.

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A titanic drug resistance threat in Cryptococcus neoformans

Cited by 56 publications

References 77 publications

Host environmental conditions induce small fungal cell size and alter population heterogeneity in Cryptococcus neoformans

Host environmental conditions induce small fungal cell size and alter population heterogeneity in Cryptococcus neoformans

Treatment strategies for cryptococcal infection: challenges, advances and future outlook

mSphere of Influence: Positive Research Culture Enables Excellence and Innovation

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