# Molecular basis of antimalarial drug resistance in Plasmodium vivax

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2024 · $60,361

## Abstract

Project Summary/Abstract
We confirm that the scope of the parent grant (R01AI168163) will remain unchanged.
Malaria parasites infect red blood cells (RBCs), within which they proliferate to cause disease in a continuous
cycle of invasion, growth, and egress from one host RBC to another. Free merozoite parasites use ligand-
receptor interactions to invade RBCs and escape the humoral immune system after egress from an infected
RBC. Plasmodium vivax, a parasite that causes malaria, exclusively invades reticulocytes, the youngest RBCs,
through these ligand-receptor interactions. The Duffy antigen receptor for chemokines (DARC) is a blood group
antigen on the RBC surface. DARC was the first identified receptor for P. vivax, binding the parasite protein P.
vivax Duffy Binding Protein (PvDBP). Genetic variations in the DARC gene, which determines the presence or
absence of Duffy antigens, affect malaria control efforts. Duffy-negative populations of African ancestry were
initially thought to resist P. vivax invasion. However, recent studies showed that Duffy-negative cells allow a
low level of DARC expression, primarily on immature reticulocytes, the presumed target of invasion by P. vivax
parasites.
There have been increasing reports of antimalarial drug resistance with P. vivax, which poses a significant
public health concern and impedes malaria control efforts and elimination programs. The mechanisms of drug
resistance in P. vivax are poorly understood, and we hypothesize that drug resistance will be influenced by
invasion into reticulocytes of different ages, cells undergoing dynamic changes to surface receptor
presentation, sub-cellular organelle composition, and metabolic capacity. Given the observation regarding
Duffy-negative invasion into immature reticulocytes, I hypothesize that the invasion of parasites into younger
reticulocytes alters sensitivity to standard antimalarial drugs. Here, I propose to (Aim 1) explore whether P.
vivax invasion into reticulocytes of different ages promotes drug resistance (in reticulocytes with and without
DARC); (Aim 2) identify reticulocyte host receptors for P. vivax using a CRISPR/Cas9-based RBC knockout
screen of candidate membrane receptors. This work is crucial for advancing 1) our knowledge of P. vivax
invasion in Duffy-negative reticulocyte populations and drug resistance mechanisms and 2) identifying novel
reticulocyte-tropic invasion pathways.

## Key facts

- **NIH application ID:** 11047291
- **Project number:** 3R01AI168163-03S1
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Manoj T Duraisingh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $60,361
- **Award type:** 3
- **Project period:** 2024-03-02 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11047291

## Citation

> US National Institutes of Health, RePORTER application 11047291, Molecular basis of antimalarial drug resistance in Plasmodium vivax (3R01AI168163-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11047291. Licensed CC0.

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