Protection of mice against experimental cryptococcosis using glucan particle-based vaccines containing novel recombinant antigens. 2020

Maureen M Hester, and Chrono K Lee, and Ambily Abraham, and Payam Khoshkenar, and Gary R Ostroff, and Stuart M Levitz, and Charles A Specht
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Meningitis due to Cryptococcus neoformans is responsible for upwards of 180,000 deaths worldwide annually, mostly in immunocompromised individuals. Currently there are no licensed fungal vaccines, and even with anti-fungal drug treatment, cryptococcal meningitis is often fatal. Our lab previously demonstrated vaccination with recombinant cryptococcal proteins delivered in glucan particles (GPs) protects mice against an otherwise lethal infection. The aim of the present study was to discover additional cryptococcal antigens affording vaccine-mediated protection. Sixteen proteins, each with evidence of extracellularity, were selected for in vivo testing based on their abundance in protective alkaline extracts of an acapsular C. neoformans strain, their known immunogenicity, and/or their high transcript level during human infection. Candidate antigens were recombinantly expressed in E. coli, purified and loaded into GPs. BALB/c and C57BL/6 mice received three subcutaneous injections of GP-based vaccine, and survival was assessed for 84 days following a lethal orotracheal challenge with strain KN99. As with our six published GP-vaccines, we saw differences in overall protection between mouse strains such that BALB/c mice typically demonstrated better survival than C57BL/6 mice. From these studies, we identified seven new proteins which, when administered as GP-vaccines, protect BALB/c and/or C57BL/6 mice against cryptococcal infection. With these results, we expand the pool of novel protective antigens to eleven proteins and demonstrate the potential for selection of highly transcribed extracellular proteins as vaccine targets. These screens highlight the efficacy of GP-subunit vaccines and identify promising antigens for further testing in anti-cryptococcal, multi-epitope vaccine formulations.

UI MeSH Term Description Entries
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D003453 Cryptococcosis Fungal infection caused by genus CRYPTOCOCCUS. C gattii Infection,C neoformans Infection,C. gattii Infection,C. neoformans Infection,Cryptococcus Infection,Cryptococcus Infections,Cryptococcus gattii Infection,Torulosis,Cryptococcus neoformans Infection,C gattii Infections,C neoformans Infections,C. gattii Infections,C. neoformans Infections,Cryptococcoses,Cryptococcus gattii Infections,Cryptococcus neoformans Infections,Infection, C gattii,Infection, C neoformans,Infection, C. gattii,Infection, C. neoformans,Infection, Cryptococcus,Infection, Cryptococcus gattii,Infection, Cryptococcus neoformans,Infections, C gattii,Infections, C. neoformans,Toruloses
D003455 Cryptococcus neoformans A species of the fungus CRYPTOCOCCUS. Its teleomorph is Filobasidiella neoformans. Blastomyces neoformans,Debaryomyces neoformans,Filobasidiella neoformans,Lipomyces neoformans,Saccharomyces neoformans,Torula neoformans,Torulopsis neoformans,Cryptococcus neoformans var. grubii
D005657 Fungal Vaccines Suspensions of attenuated or killed fungi administered for the prevention or treatment of infectious fungal disease. Vaccines, Fungal
D005936 Glucans Polysaccharides composed of repeating glucose units. They can consist of branched or unbranched chains in any linkages. Glucan,Polyglucose,Polyglucoses,Glucan (BO),Glucose Polymer,Polycose,Polymer, Glucose
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000946 Antigens, Fungal Substances of fungal origin that have antigenic activity. Fungal Antigen,Fungal Antigens,Antigen, Fungal
D013045 Species Specificity The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species. Species Specificities,Specificities, Species,Specificity, Species

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