# A structured transcriptional switching network that coordinates antigenic variation by malaria parasites

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $618,539

## Abstract

Project Summary/Abstract
Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a
disease that kills more than 400,000 people a year, mostly young children in Africa. These protozoan
parasites invade and ultimately destroy circulating red blood cells (RBCs) of their host, leading to severe
anemia and the frequently lethal syndromes of cerebral malaria and pregnancy associated malaria. Over
the course of an infection, small sub-populations of parasites arise that have an altered antigenic
phenotype, thus avoiding the antibody response of the host. This process is referred to as antigenic
variation and is responsible for the persistent nature of the disease as well as the waves of parasitemia
frequently observed in P. falciparum infections. Antigenic variation of P. falciparum infected RBCs results
from switches in expression between individual members of the multi-copy var gene family. Each var gene
encodes a different form of a protein called PfEMP1. This protein is placed on the infected RBC surface
and mediates adhesion to specific receptors found on the endothelial surfaces of the blood vessel walls of
the infected individual. This adhesion is responsible for many of the disease manifestations of infection
with P. falciparum, including both cerebral malaria and pregnancy associated malaria. Only a single var
gene is expressed at a time by any given parasite, thus determining both the antigenic phenotype of the
infected cells as well as their adhesive properties. Therefore var gene expression is at the heart of both
antigenic variation and virulence of malaria infections. The long-term objectives of this project are to
understand the molecular mechanisms that regulate var gene expression and antigenic variation by
malaria parasites. Significant work in recent years has defined many molecular aspects that maintain a
gene in the active or silent state, however the mechanisms governing switching between transcriptionally
active genes remain entirely undefined. Moreover, given that an infection can include billions of individual
parasites, how they seemingly coordinate switching events to limit activation to a single or small number of
genes at a time is completely unexplored. In contrast, uncoordinated, random switching would rapidly
exhaust the entire var repertoire. There is no evidence of communication between parasites, and there
does not appear to be a strict switching order within the var gene family, therefore how this is
accomplished remains completely mysterious. The specific aims of the project are designed to decipher
the mechanistic basis of this phenomenon. Aim 1 investigates the role of an unusual, highly conserved var
gene that appears to function as central organizing gene that coordinates switching events. Aim 2 will
determine how parasites sense the presence of a placenta and alter var gene expression to take
advantage of this unusual niche. This project will contribute to the ongoing ...

## Key facts

- **NIH application ID:** 10492500
- **Project number:** 5R01AI161299-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Kirk W Deitsch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $618,539
- **Award type:** 5
- **Project period:** 2021-09-22 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492500

## Citation

> US National Institutes of Health, RePORTER application 10492500, A structured transcriptional switching network that coordinates antigenic variation by malaria parasites (5R01AI161299-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10492500. Licensed CC0.

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