The capsule of<i>Cryptococcus neoformans</i>

Casadevall, Arturo; Coelho, Carolina; Cordero, Radamés J. B.; Dragotakes, Quigly; Jung, Eric H.; Vij, Raghav; Wear, Maggie P.

doi:10.1080/21505594.2018.1431087

Cited by 153 publications

(146 citation statements)

References 101 publications

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“…We asked whether the high efficacy of fenbendazole in vivo was related to neutralization of virulence determinants in addition to its antifungal effects. Capsule synthesis and intracellular proliferation rates have been consistently associated to the pathogenic potential of cryptococci (23, 24). We therefore evaluated whether fenbendazole was able to interfere with each of these biological events.…”

Section: Resultsmentioning

confidence: 99%

Fenbendazole controlsin vitrogrowth, virulence potential and animal infection in theCryptococcusmodel

Oliveira

Joffe

Simon

et al. 2020

Preprint

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AbstractThe human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 30 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

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Section: Resultsmentioning

confidence: 99%

Fenbendazole controlsin vitrogrowth, virulence potential and animal infection in theCryptococcusmodel

Oliveira

Joffe

Simon

et al. 2020

Preprint

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“…Increasing the yeast dosage, however, resulted in significantly reduced weight gain. This bi-phasic pattern, resembling hormesis 47 in which a low dose of an environmental agent is beneficial, while a high dose is toxic, could be due to C. neoformans ’ immunogenic capsule 48 . Caterpillars displaying variable degrees of susceptibility to different yeast species, with weight providing an additional measure of host damage, suggests that this host model is broadly applicable for the study of fungal virulence.…”

Section: Resultsmentioning

confidence: 99%

“…While tissue-specific hormetic responses have been described in flies, where a virus-acquired cytokine relays ageing 54 , and examples of abiotic factors or signalling molecules affecting peas and aphid infestation 55 , immunity in plants 56,57 , life-span in malaria-transmitting Anopheles 58 , and larval development in Black Cutworm 59 , this example here could be the first involving a eukaryotic host-pathogen relationship. The underlying factor remains to be elucidated but C. neoformans ’ highly immunogenic capsule seems to be an excellent candidate 48 .…”

Section: Discussionmentioning

confidence: 99%

Tobacco Hornworm (Manduca sexta) caterpillars as a novel host model for the study of fungal virulence and drug efficacy

Lyons

Softley

Balfour

et al. 2019

Preprint

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29Pathogenic yeast species can cause life-threatening infections in humans. The two leading 30 yeast pathogens, Candida albicans and Cryptococcus neoformans, cause systemic infections 31 in >1.4 million patients world-wide with mortality rates approaching 75%. It is thus 32 imperative to study fungal virulence mechanisms, stress response pathways, and the efficacy 33 of antifungal drugs. This is commonly done using mammalian models. To address ethical and 34 practical concerns, invertebrate models, such as wax moth larvae, nematodes, or flies, have 35 been introduced over the last two decades. To address short-comings in existing invertebrate 36 host models, we developed fifth instar caterpillars of the Tobacco Hornworm moth Manduca 37 sexta as a novel host model for the study of fungal virulence and drug efficacy. These 38 caterpillars can be raised at standardised conditions, maintained at 37˚C, can be injected with 39 defined amounts of yeast cells, and are susceptible to the most threatening yeast pathogens, 40 including C. albicans, C. neoformans, C. auris, and C. glabrata. Infected caterpillars can be 41 rescued by treatment with commonly deployed antifungal drugs and importantly, fungal 42 burden can be assessed daily throughout the course of infection in a single caterpillar's faeces 43 and hemolymph. Notably, these animals are large enough so that weight provides a reliable 44 and reproducible measure of fungal virulence. This model combines a suite of parameters that 45 recommend it for the study of fungal virulence. 46 47 50 tuberculosis 1 . The leading yeast pathogens, Candida albicans and Cryptococcus neoformans, 51 together account for >1,400,000 life-threatening infections world-wide with mortality rates 52 approaching 75% 1 . Candidemia, most commonly caused by C. albicans, is the fourth most 53 common cause of nosocomial blood stream infections, only surpassed by infections with 54Staphylococci and Enterococcus spp. Disturbingly, candidemia incidence rates are on the 55 rise. Within less than ten years, incidence rates increased by 36% 2 . Although cryptococcosis 56 incidence rates are on the decline in North America, this AIDS-defining illness is responsible 57 for 15% of all AIDS-related deaths world-wide 2,3 . This already dire situation is further 58 confounded by the emergence of drug resistant yeast species. Patients at risk of developing 59 invasive candidemia are often prophylactically treated with fluconazole, while the 60 echinocandins are considered a first line defence strategy 4 . Yet, C. glabrata, the most 61 3 common non-albicans Candida species associated with nosocomial blood stream infections 5 , 62 is intrinsically less susceptible to azole drugs and acquires resistance to echinocandins 63 rapidly 6 . The rapid global spread of multi-drug resistant C. auris has further exacerbated the 64 threat posed by fungi. C. auris was first reported in 2009 in Japan 7 . In 2015, C. auris arrived 65 in Europe causing an outbreak involving 72 patients in a cardio-thoracic hospital i...

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“…Consequently, CAN2 is dispensable for growth at 5% CO 2 and virulence in a murine host (10). Host CO 2 concentrations, however, have a profound effect on C. neoformans biology because they induce capsule formation (7). Indeed, our hypothesis that host concentrations of CO 2 are a significant stress to C. neoformans is supported by the fact that Granger et al noted that the growth of cultures slowed considerably after being shifted to host CO 2 concentrations to induce capsule formation (8).…”

Section: Introductionmentioning

confidence: 99%

Host carbon dioxide concentration is an independent stress for Cryptococcus neoformans that affects virulence and antifungal susceptibility

Krysan

Zhai

Beattie

et al. 2019

Preprint

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The ability of Cryptococcus neoformans to cause disease in humans varies significantly among strains with highly related genotypes. In general, environmental isolates of pathogenic species such as C. neoformans var. grubii have reduced virulence relative to clinical isolates, despite having no differences in the expression of the canonical virulence traits (high temperature growth, melanization and capsule formation). In this observation, we report that environmental isolates of C. neoformans tolerate host CO2 concentrations poorly compared to clinical isolates and that CO2 tolerance correlates well with the ability of the isolates to cause disease in mammals. Initial experiments also suggest that CO2 tolerance is particularly important for dissemination of C. neoformans from the lung to the brain. Furthermore, CO2 concentrations affect the susceptibility of both clinical and environmental C. neoformans isolates to the azole class of antifungal drugs, suggesting that antifungal testing in the presence of CO2 may improve the correlation between in vitro azole activity and patient outcome.ImportanceA number of studies comparing either patient outcomes or model system virulence across large collections of Cryptococcus isolates have found significant heterogeneity in virulence even among strains with highly related genotypes. Because this heterogeneity cannot be explained by variations in the three well-characterized virulence traits (growth at host body temperature; melanization; and polysaccharide capsule formation), it has been widely proposed that additional C. neoformans virulence traits must exist. C. neoformans natural niche is in the environment where the carbon dioxide concentration is very low (∼0.04%); in contrast, mammalian host tissue carbon dioxide concentrations are 125-fold higher (5%). We have found that the ability to grow in the presence of 5% carbon dioxide distinguishes low virulence strains from high virulence strains, even those with a similar genotype. Our findings suggest that carbon dioxide tolerance is a previously un-recognized virulence trait for C. neoformans.

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The capsule ofCryptococcus neoformans

Cited by 153 publications

References 101 publications

Fenbendazole controlsin vitrogrowth, virulence potential and animal infection in theCryptococcusmodel

Fenbendazole controlsin vitrogrowth, virulence potential and animal infection in theCryptococcusmodel

Tobacco Hornworm (Manduca sexta) caterpillars as a novel host model for the study of fungal virulence and drug efficacy

Host carbon dioxide concentration is an independent stress for Cryptococcus neoformans that affects virulence and antifungal susceptibility

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