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Principal Investigator: Kacie McCarty
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $41,614
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Microsporidia are an early diverging group of fungal pathogens that infect a wide variety of hosts ranging from
insects to humans. Encephalitozoon intestinalis is one of the main human-infecting species of microsporidia
which causes diarrhea and wasting syndrome in patients and can be fatal in immunocompromised individuals.
As an obligate, intracellular pathogen, E. intestinalis has evolved a highly reduced genome resulting in the loss
of many regulatory and metabolic pathways, driving these parasites to rely solely on their hosts for metabolites.
Upon infection, E. intestinalis replicates in a membrane bound compartment called the parasitophorous
vacuole (PV) which serves as a protective barrier from the host. How E. intestinalis generates the PV
membrane, acquires nutrients from the host, and develops within the PV remains elusive. E. intestinalis likely
establishes a replication permissive niche and modulates host cellular processes such as vesicle trafficking,
metabolite biosynthesis, and programmed cell death. Using serial block face scanning electron microscopy we
have been able to gain insight into the replicative niche as well as the developmental stages of the parasite
within the PV. Our data reveal that the PV nestles closely against the host mitochondria and host nucleus
during infection suggesting that there are protein interactions occurring between the PV and host organelles.
However, it is not known which parasite proteins localize to the PV membrane, and how these interact with
host proteins or whether specific host proteins are recruited and transported to the PV compartment. Using
cellular, proteomic, and structural approaches I will provide the first glimpse into the molecular and cellular
features of the PV compartment and the parasites within. I will identify PV associated proteins using mass
spectrometry and characterize their role in perturbing host cellular pathways and promoting parasite
development (aim 1). I will also investigate the ultrastructure of the PV at high resolution including the
complexes formed between the PV and host organelles and the ultrastructure of the developing parasites
within the PV via cryo-electron tomography (aim 2). These results will provide insight into the mechanisms of
host-parasite driven compartment formation, host cell manipulation, and parasite development.
Terms: <Anabolism><Apoptosis><Apoptosis Pathway><Binding><Biotinylation><Carrier Proteins><Cell Body><Cell Function><Cell Nucleus><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Complex><Cryo-electron tomography><Data><Development><Diarrhea><Disease><Disorder><E intestinalis><E. intestinalis><Encephalitozoon (Septata) intestinalis><Encephalitozoon intestinalis><Environment><Face><Generations><Genome><Host Defense Mechanism><Host Factor><Host Factor Protein><Human><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Individual><Infection><Insecta><Insects><Insects Invertebrates><Integration Host Factors><Knock-out><Knockout><Maintenance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Pathway><Methods><Microspora><Microspora Infections><Microsporea><Microsporida><Microsporidia><Microsporidiosis><Mitochondria><Modern Man><Molecular><Molecular Interaction><Morphology><Nuclear><Nucleus><Nutrient><Organelles><P falciparum><P. falciparum><P.falciparum><Parasites><Pathway interactions><Patients><Plasmodium falciparum><Process><Programmed Cell Death><Protein Secretion><Protein Trafficking><Proteins><Proteome><Proteomics><Regulatory Pathway><Reproduction spores><Resolution><Role><S intestinalis><S. intestinalis><Scanning Electron Microscopy><Septata intestinalis><Site><Spores><Structure><Subcellular Process><Surface><Surface Proteins><Symptoms><Transport Protein Gene><Transport Proteins><Transporter Protein><Tube><Vacuole><Vesicle><Visualization><Wasting Disease><Wasting Syndrome><Work><biosynthesis><burden of disease><burden of illness><cryo-EM tomography><cryoEM tomography><cryoelectron tomography><developmental><disease burden><electron cryo-tomography><faces><facial><fungal pathogen><fungi pathogen><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><immunosuppressed patient><insight><membrane structure><mitochondrial><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><non-genetic><nongenetic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathogen><pathogenic fungus><pathway><permissiveness><protein complex><protein transport><recruit><resolutions><small molecule><social role><timeline><tool><trafficking><wasting condition><wasting disorder>