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NIH grant 1R21AI193585-01A1: Parasitophorous vacuole biogenesis during Plasmodium invasion into erythrocytes
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Vasant Muralidharan. Award: $181578.
Start: 2026-09-11T00:00:00.
Project Summary
The obligate intracellular parasite Plasmodium falciparum causes malaria and is responsible for nearly
600,000 deaths every year. The clinical symptoms of malaria are caused by the exponential asexual
growth of parasites within human red blood cells. This cycle begins with the invasion of P. falciparum into
the erythrocyte, where it hides within a vacuole (parasitophorous vacuole or PV) to divide into daughter
merozoites and ends with the rapid release of merozoites that invade a red blood cell (RBC) to start the
cycle anew. As the merozoite invades the RBC, the RBC membrane folds over the merozoite. When the
merozoite is completely internalized, this inside-out RBC membrane fuses to form the PV. Fusion of
biological membranes is an energetically expensive process that is highly regulated. Many intracellular
pathogens hijack host membrane remodeling mechanisms to enter their host cell and expand within these
host-derived vacuoles. However, the RBC does not have any membrane trafficking mechanisms, and
therefore, Plasmodium parasites cannot repurpose host mechanisms of membrane fusion to form the
PV. The process of PV formation was observed by electron microscopy nearly fifty years ago, but a
central question, how does the RBC membrane fuse to form the PV, remains unanswered.
The proposed research focuses on a conserved membrane protein expressed in late schizonts that
has distant homology to vesicle-SNAREs, which mediate membrane fusion in other well-studied
organisms. Our preliminary data show that we have successfully generated conditional mutants for this
SNARE-like protein and data show that it localizes to rhoptry neck (SNARE-like rhoptry neck protein or
SNARON). These data show that SNARON is required to complete the invasion of P. falciparum
merozoites into the RBC. In the absence of SNARON, almost fully internalized merozoites are ejected
from the RBC. We have developed time-lapse imaging assays to observe merozoite invasion and
coupled with lipid-dye labeled RBCs allow us to observe the formation of the PV during invasion. The
proposed research will focus on elucidating the role of SNARON in the biogenesis of the PV during
merozoite invasion. SNARON has been expressed in yeast and its biochemical function in membrane
fusion will be determined using mutant yeast that are deficient in membrane fusion mechanisms. Assays
using recombinantly purified SNARON will establish its role in membrane biology. Since Plasmodium are
obligate parasites that grow within vacuoles in both erythrocytic and exo-erythrocytic life cycle stages,
these studies may provide pan-active targets for antimalarial development.document fetched 2026-09-20 02:42