Is Development of a Vaccine against Cryptococcus neoformans Feasible?

Wager, Chrissy M. Leopold; Wormley, Floyd L.

doi:10.1371/journal.ppat.1004843

Cited by 24 publications

(14 citation statements)

References 32 publications

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“…Spores or desiccated yeast cells of C. neoformans enter the host through the respiratory tract, from which uncontrolled infection disseminates to the central nervous system and causes fatal meningitis (1-4). However, the existing treatments for cryptococcosis are generally ineffective in immune-compromised patients with impaired adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection

Flaczyk

Neal

et al. 2017

The Journal of Immunology

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Scavenger receptor MARCO promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen Cryptococcus neoformans, remains unknown. Using a mouse model of C. neoformans infection we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO-/- mice was accompanied by impaired recruitment of Ly6Chigh monocytes and monocyte-derived dendritic cells (moDC) and lower moDC co-stimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO-/- mice was linked to diminished early expression of INF-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2-axis during C. neoformans infection. Lastly, we found that MARCO was involved in C. neoformans phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between C. neoformans and lung resident cells and promotes the production of CCR2-ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.

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Section: Introductionmentioning

confidence: 99%

Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection

Flaczyk

Neal

et al. 2017

The Journal of Immunology

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“…Populations that could be targeted for vaccination include the following: (i) HIV-infected persons; (ii) persons on medications which suppress T cells (particularly transplant recipients); (iii) persons living in regions where C. gattii is endemic; and (iv) persons with other high-risk diseases (e.g., sarcoidosis, lymphoma). Preclinical approaches to developing cryptococcal vaccines have included immunization with protein-GXM conjugates and peptide mimetics of GXM designed to elicit antibody-mediated protection, as well as live and killed C. neoformans strains ( 9 – 15 ). Other work has focused on the identification of C. neoformans antigens that stimulate protective T cell responses.…”

Section: Introductionmentioning

confidence: 99%

Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles ContainingCryptococcusAlkaline Extracts

Specht

Lee

Huang

et al. 2015

mBio

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A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purified Saccharomyces cerevisiae cell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains of C. neoformans and C. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4+ T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine.

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“…Cryptococcosis is the most fungal infection in immunocompromised individuals especially who's with HIV infection, cancer or solid organ transplantation patients. Very serious complications starting from severe pulmonary infection until fatal meningoencephalitis were reported [51][52][53][54]. High cost of Cryptococcosis treatment and some clinical consequences like toxicity and antifungal resistance [14,55] lead to exhibiting a strong prolonged preventive approach.…”

Section: Discussionmentioning

confidence: 99%

Design of an epitope-based peptide vaccine againstCryptococcus neoformans

Khalil

Omer

Iza

et al. 2018

Preprint

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Introduction:This study aimed to design an immunogenic epitope for Cryptococcus neoformans the etiological agent of cryptococcosis using in silico simulations, for epitope prediction, we selected the mannoprotein antigen MP88 which it's known to induce protective immunity. Material &method:A total of 39 sequences of MP88 protein with length 378 amino acids were retrieved from the National Center for Biotechnology Information database (NCBI) in the FASTA format were used to predict antigenic B-cell and T cell epitopes via different bioinformatics tools at Immune Epitope Database and Analysis Resource (IEDB). The tertiary structure prediction of MP88 was created in RaptorX, and visualized by UCSF Chimera software. Result:A Conserved B-cell epitopes AYSTPA, AYSTPAS, PASSNCK, and DSAYPP have displayed the most promising B cell epitopes. While the YMAADQFCL, VSYEEWMNY and FQQRYTGTF they represent the best candidates T-cell conserved epitopes, the 9-mer epitope YMAADQFCL display the greater interact with 9 MHC-I alleles and HLA-A*02:01 alleles have the best interaction with an epitope. The VSYEEWMNY and FQQRYTGTF they are nonallergen while YMAADQFCL was an allergen. For MHC class II peptide binding prediction, the YARLLSLNA, ISYGTAMAV and INQTSYARL represent the most Three highly binding affinity core epitopes. The core epitope INQTSYARL was found to interact with 14 MHC-II. The allergenicity prediction reveals ISYGTAMAV, INQTSYARL were non-allergen and YARLLSLNA was an allergen. Regarding population coverage the YMAADQFCL exhibit, a higher percentage among the world (69.75%) and the average population coverage was 93.01%. In MHC-II, ISYGTAMAV epitope reveal a higher percentage (74.39%) and the average population coverage was (81.94%). This successfully designed a peptide vaccine against Cryptococcus neoformans open up a new horizon in Cryptococcus neoformans research; the results require validation by in vitro and in vivo experiments.

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Is Development of a Vaccine against Cryptococcus neoformans Feasible?

Cited by 24 publications

References 32 publications

Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection

Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection

Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles ContainingCryptococcusAlkaline Extracts

Design of an epitope-based peptide vaccine againstCryptococcus neoformans

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