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Principal Investigator: Xiaorong Lin
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2024
Award: $577,663
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Cryptococcal meningoencephalitis (CME) is responsible for more than 15% of the total deaths of AIDS
patients. The disease claims hundreds of thousands of lives each year, with global mortality rates of ~70%
despite antifungal therapies. Unfortunately, there is no vaccine clinically available for cryptococcosis. The
challenges of preventing and treating this fungal disease motivate our investigation of cryptococcal pathways
that can induce a strong protective host response. The encapsulated fungus Cryptococcus neoformans is
known to undergo yeast-to-filament morphological transition. We previously showed that morphotype of this
fungus has a profound effect on its interaction with various hosts. In mammalian models of cryptococcosis, the
yeast form is pathogenic while the filamentous form is not. We established that the transcription factor Znf2,
which drives filamentous growth, is a powerful anti-virulence regulator. Cryptococcal cells overexpressing
ZNF2 (ZNF2oe) are avirulent and elicit strong and long-lasting protective immunity, which serves as an effective
vaccine against subsequent lethal challenges. Importantly, we showed that once mice are vaccinated with
ZNF2oe cells, their CD4+ T cells are dispensable for protection at the time of fungal challenge (mimic
people with HIV prior to AIDS). Furthermore, vaccination with ZNF2oe cells even in hosts with pre-
existing CD4+ T cell deficiency is also protective against cryptococcosis (mimic AIDS patients). These
findings are important because the majority of cryptococcosis patients are AIDS patients with low CD4+ T cell
counts, and our preclinical studies suggest that cryptococcal vaccines could be effective in these individuals.
The long-term goal of this project is to characterize the filamentation pathway and explore it for
therapeutics (e.g. vaccines). We have made significant progress in establishing the link between morphotype,
virulence and immunity, and discovered multiple regulators required for both Znf2-directed filamentation and
Znf2-induced host immunity. Recently, we also identified mutations that block Znf2's function in filamentation,
but do not affect its ability to induce host protective effects. These findings provide a unique opportunity to
pinpoint cryptococcal factors associated with host protective effect of Znf2. Because ZNF2oe in both heat-
inactivated and live cells provides host protection, we predicted that extracellular components of ZNF2oe cells
are important protective immunogens. Consistently, host protection elicited by ZNF2oe cells depends on the
capsule where extracellular antigens are localized. Additionally, our preliminary data revealed that some
antigens are secretory proteins including several glycosylphosphatidylinositol (GPI)-anchored glycoproteins.
Capitalizing on these discoveries and our expertise in mRNA lipid nanoparticle (mRNA-LNP) technology, we
aim to (1) define cryptococcal factors that are important for Znf2's anti-virulence effect; (2) identify
immunogens that elicit protective host responses; and (3) use selected immunogens to develop
mRNA-LNP or recombinant protein vaccines against cryptococcosis.
Terms: <AIDS><AIDS Virus><AIDS/HIV><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Affect><Animals><Antifungal Therapy><Antigens><Basal Transcription Factor><Basal transcription factor genes><Binding><C albicans><C neoformans><C. albicans><C. neoformans><C.albicans><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Candida albicans><Capsules><Cell Body><Cell Components><Cell Count><Cell Number><Cell Protection><Cell Structure><Cell surface><Cells><Cellular Structures><Cerebromeningitis><Cessation of life><Chromatin><Class II Antigens><Class II Major Histocompatibility Antigens><Clinical><Coupled><Cryptococcosis><Cryptococcus><Cryptococcus neoformans><Cytoprotection><DNA Chips><DNA Microarray><DNA Microarray Chip><DNA Microarray format><DNA Microchips><DNA seq><DNA sequencing><DNAseq><Data><Death><Death Rate><Disease><Disorder><Drops><Encapsulated><Encephalomeningitis><Filament><Funding><GPI Membrane Anchors><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Glycoinositol Phospholipid Membrane Anchor><Glycoproteins><Glycosyl-Phosphatidylinositol Membrane Protein Anchors><Glycosylphosphatidylinositol Anchors><Goals><Growth><HIV><HIV/AIDS><Histocompatibility Antigens Class II><Human Immunodeficiency Viruses><I-A Antigen><Ia Antigens><Ia-Like Antigens><Immune Response Antigens><Immune mediated therapy><Immune response><Immune-Response-Associated Antigens><Immunity><Immunological response><Immunologically Directed Therapy><Immunotherapy><Individual><Investigation><LAV-HTLV-III><Link><Liposomal><Liposomes><Lymphadenopathy-Associated Virus><MHC Class II Molecule><MHC Class II Protein><MHC class II antigen><Major Histocompatibility Complex Class II><Meningoencephalitis><Messenger RNA><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Morphogenesis><Morphology><Murine><Mus><Mutation><Opportunistic Infections><Pathogenicity><Pathway interactions><Patients><Peptides><Persons><Phagocytosis><Phase><Proteomics><Public Health><RNA Seq><RNA sequencing><RNAseq><Recombinant Proteins><Regulation><Regulon><Research><Risk><T-Cell Depletion><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Technology><Testing><Therapeutic><Time><Tissue Growth><Torula><Torulosis><Transcription Factor Proto-Oncogene><Transcription factor genes><Vaccinated><Vaccination><Vaccines><Virulence><Virulent><Virus-HIV><Yeasts><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><access to vaccination><access to vaccines><capsule><cell type><comparative><critical period><cytoprotective><develop a vaccine><develop vaccines><development of a vaccine><extracellular><fungal infectious disease treatment><fungal pathogen><fungi pathogen><fungus><genetic approach><genetic strategy><genome mutation><host response><hypoimmunity><immune deficiency><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunodeficiency><immunogen><immunogenicity><immunoresponse><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><morphogenetic process><mortality rate><mortality ratio><mouse model><murine model><novel><ontogeny><overexpress><overexpression><pathogen><pathogenic fungus><pathway><pre-clinical study><preclinical study><prevent><preventing><protective effect><protective factors><secretory protein><transcription factor><transcriptome sequencing><transcriptomic sequencing><vaccination access><vaccination availability><vaccine access><vaccine availability><vaccine candidate><vaccine development>