Mechanisms of Pulmonary Escape and Dissemination by Cryptococcus neoformans

Denham, Steven T; Brown, Jessica C. S.

doi:10.3390/jof4010025

Cited by 54 publications

(52 citation statements)

References 137 publications

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“…This (acidic environment), however, does not seem to inhibit the growth of these cells, which suggests that C. neoformans is well adapted to low pH [57]. In part, this adaptation to acidic pH is beneficial to cryptococcal cells in that it allows them access to iron [106,107], which is inaccessible at neutral pH due to iron being bound to transferrin [108].…”

Section: Ph Tolerancementioning

confidence: 99%

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

et al. 2020

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The ability of microorganisms to colonise and display an intracellular lifestyle within a host body increases their fitness to survive and avoid extinction. This host–pathogen association drives microbial evolution, as such organisms are under selective pressure and can become more pathogenic. Some of these microorganisms can quickly spread through the environment via transmission. The non-transmittable fungal pathogens, such as Cryptococcus, probably return into the environment upon decomposition of the infected host. This review analyses whether re-entry of the pathogen into the environment causes restoration of its non-pathogenic state or whether environmental factors and parameters assist them in maintaining pathogenesis. Cryptococcus (C.) neoformans is therefore used as a model organism to evaluate the impact of environmental stress factors that aid the survival and pathogenesis of C. neoformans intracellularly and extracellularly.

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Section: Ph Tolerancementioning

confidence: 99%

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

et al. 2020

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“…Although a well-balanced regulation of the immune cell network protects from fatal outcomes in pulmonary cryptococcosis, the precise immunological mechanisms that direct the development of protective or detrimental anticryptococcal immunity are not clearly understood. However, numerous studies in mice clearly indicated that the control and clearance of C. neoformans is strongly reliant on prototypic type 1 immune responses, characterized by the production of inflammatory cytokines such as Interleukin (IL)-2, Tumor necrosis factor (TNF), and particularly Interferon (IFN)-γ as well as the activation of classical macrophages [reviewed in (8)]. Conversely, type 2 biased immune responses have been implicated in disease progression and detrimental outcomes (8).…”

Section: Introductionmentioning

confidence: 99%

“…However, numerous studies in mice clearly indicated that the control and clearance of C. neoformans is strongly reliant on prototypic type 1 immune responses, characterized by the production of inflammatory cytokines such as Interleukin (IL)-2, Tumor necrosis factor (TNF), and particularly Interferon (IFN)-γ as well as the activation of classical macrophages [reviewed in (8)]. Conversely, type 2 biased immune responses have been implicated in disease progression and detrimental outcomes (8). At mucosal surfaces, the release of alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) was identified as important early trigger of type 2 immunity, which is defined by production of the cytokines IL-4, IL-5, and IL-13 [reviewed in (9)(10)(11)].…”

Section: Introductionmentioning

confidence: 99%

Group 2 Innate Lymphoid Cells (ILC2) Suppress Beneficial Type 1 Immune Responses During Pulmonary Cryptococcosis

et al. 2020

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“…Cryptococcus neoformans is worldwide opportunistic human fungal pathogen causing life-threatening pneumonia and meningitis in immunocompromised and immunocompetent individuals (1, 2). Cryptococcosis occurs when desiccated yeast or spores are inhaled, proliferate in the host lung and further disseminate into the central nervous system (2, 3). In response to the earliest interactions with host lung stimuli , C. neoformans cells undergo an unusual morphogenic switch, changing from small haploid yeast to large polyploid titan cells (4–9).…”

Section: Introductionmentioning

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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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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Mechanisms of Pulmonary Escape and Dissemination by Cryptococcus neoformans

Cited by 54 publications

References 137 publications

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

Group 2 Innate Lymphoid Cells (ILC2) Suppress Beneficial Type 1 Immune Responses During Pulmonary Cryptococcosis

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

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