A Predicted Mannoprotein Participates in Cryptococcus gattii Capsular Structure

Reuwsaat, Júlia Catarina Vieira; Motta, Heryk; Garcia, Ane Wichine Acosta; Vasconcelos, Carolina Bettker; Marques, Bárbara Machado; Oliveira, Natalia Kronbauer; Rodrigues, Jéssica; Ferrareze, Patrícia Aline Gröhns; Frasés, Susana; Lopes, William; Barcellos, Vanessa Abreu; Squizani, Eamim Daidrê; Horta, Jorge André; Schrank, Augusto; Rodrigues, Márcio L.; Staats, Charley Christian; Vainstein, Marilene Henning; Kmetzsch, Lívia

doi:10.1128/msphere.00023-18

Cited by 17 publications

(13 citation statements)

References 84 publications

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“…The fungal cell wall made up of α and β glucans, chitin, chitosan, and mannoproteins, is vital for fungal growth and development and is also one of the most significant drug development targets [36,37]. The results of previous studies showed that mannoproteins play a vital role in fungal virulence or cell wall integrity, such as Cig1 in C. neoformans, Krp1 in C. gattii, and Mp1p in T. marneffei [21,22,26]. Given mannoproteins' role in fungal virulence or cell wall integrity in fungal pathogens, it might be one of the potential targets for antifungal drug development.…”

Section: Discussionmentioning

confidence: 99%

“…Cadieux et al showed that the C. neoformans mannoprotein Cig1 helps get iron from heme and further proved that the Cig1 and the ferroxidase Cfo1 jointly regulate the virulence of C. neoformans [21]. Reuwsaat et al found that the predicted mannoprotein Krp1 is required for the cell wall structural integrity but is not necessary for fungal virulence in vivo in C. gattii [22]. Viudes et al found that Candida albicans surface mannoprotein MP58 could elicit a strong antibody response during infection.…”

Section: Introductionmentioning

confidence: 99%

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A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

Han

Liu

2020

Pathogens

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The capsule of the fungal pathogen Cryptococcus neoformans consists of glucuronoxylomannan (GXM), glucuronoxylomannogalactan (GXMGal), and mannoproteins (MPs). MPs are a kind of glycoproteins with low content but high immunogenicity, which can stimulate the immune protection of the host. However, there is not much information about the role of mannoproteins in virulence of the human fungal pathogen C. neoformans. In this study, we reported the identification and functional analysis of a predicted mannoprotein Cmp1 that regulates fungal virulence in C. neoformans. Gene expression pattern analysis indicates that the CMP1 gene was ubiquitously expressed at all stages of cryptococcal development. Subcellular localization analysis indicated that Cmp1 was localized in the cytoplasm of cryptococcal cells. Disruption or overexpression of CMP1 results in impairing capsule formation in Cryptococcus, but it does not affect the melanin production and sensitivity under various stress conditions, nor does it affect the sexual reproduction process of Cryptococcus. Survival assay showed that the pathogenicity of the cmp1Δ mutant or the CMP1 overexpression strain was significantly attenuated in a murine inhalation model of cryptococcosis. In conclusion, our findings implied that the mannoprotein Cmp1 is required for the virulence of C. neoformans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

Han

Liu

2020

Pathogens

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“…After incubation, cells were fixed in 4% paraformaldehyde and washed three times with PBS. C. neoformans cells were placed on glass slides and mixed with similar volumes of India ink, and the capsule was measured as previously described ( 104 ).…”

Section: Methodsmentioning

confidence: 99%

The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

Reuwsaat

Agustinho

Motta

et al. 2021

mBio

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Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host, C. neoformans undergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1, and Liv3; the transcription factors Stb4, Zfc3, and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling and C. neoformans virulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination of pdr802 mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity. IMPORTANCE The pathogenic yeast Cryptococcus neoformans presents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled, C. neoformans initiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here, we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact on C. neoformans virulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings significantly advance our understanding of a serious disease.

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“…As well as common pathogenic fungi, cryptococcal cells express highly mannosylated proteins, referred to as mannoproteins (MPs), on the cell surface and can secrete them to the extracellular space during infection. 47,48) Cryptococcal cells require MPs for infection to progress and therefore MPs are feasible targets for vaccine antigens. In contrast to CPs, MPs are T-cell dependent (TD) antigens, and vaccines containing cryptococcal MPs likely induce CMI and AMI for protection against cryptococcosis.…”

Section: Mannoproteinsmentioning

confidence: 99%

Vaccines and Protective Immune Memory against Cryptococcosis

Ueno

Yanagihara

Shimizu

et al. 2020

Biological & Pharmaceutical Bulletin

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Cryptococcosis is a potentially lethal disease caused by fungal pathogens including Cryptococcus neoformans and Cryptococcus gattii species complex. These fungal pathogens live in the environment and are associated with certain tree species and bird droppings. This infectious disease is not contagious, and healthy individuals may contract cryptococcal infections by inhaling the airborne pathogens from the environment. Although cleaning a contaminated environment is a feasible approach to control environmental fungal pathogens, prophylactic immunization is also considered a promising method to regulate cryptococcal infections. We review the history of the development of cryptococcal vaccines, vaccine components, and the various forms of immune memory induced by cryptococcal vaccines.

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A Predicted Mannoprotein Participates in Cryptococcus gattii Capsular Structure

Cited by 17 publications

References 84 publications

A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

Vaccines and Protective Immune Memory against Cryptococcosis

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