# Innate Immune Training by Human Malaria

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $199,943

## Abstract

Malaria poses an enormous health problem worldwide, causing approximately 200 million new cases annually
with disease spectrum ranging from asymptomatic parasitemia to severe malaria and death. Peripheral blood
monocytes are a dynamic cell population that are rapidly recruited to sites of infection and play a key role at
the interface between innate and adaptive immunity. While activation of the innate immune response is
necessary to control blood stage infection, excessive activation of monocytes and other innate immune cells
contributes to malaria pathogenesis. Studies have demonstrated memory phenotypes in innate immunity.
Upon interaction with pathogens, innate immune cells undergo epigenetic changes that result in cellular
reprogramming and altered responses to subsequent challenge. Depending on the dose and type of initial
stimulus, epigenetic reprogramming can lead to “training” with increased pro-inflammatory cytokine responses,
or to “tolerance” with diminished pro-inflammatory cytokine responses to a subsequent stimulus. In our
preliminary data, we found that monocytes from Kenyan children experiencing acute uncomplicated malaria
and upon recovery 6 weeks later produced high levels of pro-inflammatory cytokines to TLR agonists, a
phenotype consistent with “trained” innate immunity. We hypothesize that malaria causes epigenetic changes
in monocyte precursors that modify specific gene signaling pathways important to innate immune functions.
Low parasite loads in uncomplicated malaria lead to innate immune training whereas high parasite loads in
severe malaria lead to innate immune paralysis (tolerance). Using previously collected samples from our
longitudinal studies of children with acute uncomplicated malaria and samples from our ongoing severe malaria
study in Western Kenya, we will decipher the gene pathways important in monocyte function utilizing DNA
methylation arrays combined with RNA-Seq examination of gene expression. These epigenetic and
transcriptomic changes will be coupled with ex vivo monocyte challenge to determine immune memory
phenotypes (trained vs. tolerance) and persistence over time in Kenyan children. This research is a joint effort
of investigators with experience and training in malaria biology and epidemiology, clinical medicine, monocyte
immunology, genomic technology, and bioinformatics. Results from these high-yield innovative studies will
address fundamental gaps in our understanding of the mechanisms of innate immunity to malaria and identify
specific host pathways that may become targets of adjunct therapies to antimalarial drug treatment of
uncomplicated and severe malaria.

## Key facts

- **NIH application ID:** 9963140
- **Project number:** 5R21AI139898-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** ARLENE DENT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,943
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963140

## Citation

> US National Institutes of Health, RePORTER application 9963140, Innate Immune Training by Human Malaria (5R21AI139898-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9963140. Licensed CC0.

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