# Mechanisms of environmental sensing and responses by malaria parasites

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $745,853

## Abstract

Project Summary/Abstract
Malaria continues to cause substantial morbidity and mortality throughout the developing world. The
development of resistance to newly deployed drugs as well as the lack of an effective vaccine indicate that
this disease will continue to plague mankind for the foreseeable future. It is caused by infection with
mosquito-borne parasites of the genus Plasmodium, with the species P. falciparum being responsible for
the most severe form of the disease. These parasites utilize a process called antigenic variation to avoid
the adaptive immune response of their host and thus maintain long-term, chronic infections that can last
over a year. Such lengthy infections provide the parasites with ample opportunities to be transmitted to
additional human hosts through blood feeding by Anopheline mosquitoes. Infection of mosquitoes requires
the differentiation of parasites into male and female gametocytes, a process that involves a cascade of
gene expression that initiates with the expression of a master regulator of sexual differentiation called
PfAP2-G. Both antigenic variation and sexual differentiation result from highly regulated mechanisms of
gene activation and silencing that are controlled epigenetically through changes in histone methylation
patterns at key positions in the genome. These changes in gene expression have been presumed to
happen stochastically, occurring at a rate that has evolved to provide the parasites with the best
opportunity for successful transmission between hosts. In this proposal, we explore the possibility that
rather than occurring stochastically, changes in gene expression that lead to both antigenic variation and
sexual differentiation occur in response to changes in the parasite's environment. For antigenic variation,
we hypothesize that parasites can sense rising antibody titers that recognize var gene-encoded RBC
surface antigens, triggering switching of expression to alternative members of the var gene family.
Similarly, we hypothesize that parasites can sense when they invade erythrocyte precursor cells and
respond by committing to sexual differentiation through the activation of the gene encoding PfAP2-G. This
results in preferential development of gametocytes in reticulocytes and in the bone marrow, as has been
observed in vivo. We have identified a metabolic pathway that links both of these responses to changes in
intracellular stores of the universal methyl donor, S-adenosylmethionine. Through simple manipulations of
the availability of key nutrients that feed into this pathway, we can trigger either var gene switching or
sexual commitment in cultured parasites. The specific aims of the project are designed to investigate how
changes in nutrient availability are translated into changes in intracellular S-adenosylmethionine, how
these changes affect histone methylation patterns at var genes and pfap2-g, and to identify the
physiological conditions that trigger var gene switching or sexual commi...

## Key facts

- **NIH application ID:** 9928355
- **Project number:** 5R01AI138499-03
- **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:** 2020
- **Award amount:** $745,853
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928355

## Citation

> US National Institutes of Health, RePORTER application 9928355, Mechanisms of environmental sensing and responses by malaria parasites (5R01AI138499-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928355. Licensed CC0.

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