# Understanding immune regulation in blood-stage malaria

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $441,940

## Abstract

Abstract
Malarial remains a global health burden that impacts >40% of humans. Although bed nets and antimalarial
drugs have reduced the incidence and severity of malaria, ~200,000,000 cases still occur annually with high
mortality in children from sub-Saharan Africa. Additionally, front line drug therapies are now threatened by
spread of resistant parasites. Thus, new approaches to effective vaccines and therapeutics are in need. A
critical limitation is our incomplete understanding of how the parasite manipulates host immune responses to
permit chronic and recurring blood-stage infections. We used rodent malaria models to evaluate the cellular
dynamics of the CD4 T cell and B cell responses generated during chronic blood-stage infection and then
compared these findings to humans living in endemic areas. These studies reveal that Tregs, which expand in
both humans and rodents during blood-stage malaria, interfere with conventional T helper (Th) responses and
the Follicular T helper (Tfh) cell:B cell partnership in germinal centers. Importantly, the negative impact of
Tregs occurs in a previously unrecognized but critical temporal window after infection to impede protective
immunity, through CTLA-4. Precisely timed targeting of Tregs or CTLA-4 enhanced immune responses,
accelerated clearance, and generated species-transcending immunity to blood-stage malaria. Thus, our
preliminary data uncover a critical mechanism of immune-suppression associated with blood-stage malaria. A
full understanding of the cellular and molecular basis for compromised immunity in blood-stage malaria is the
long-term goal of this competitive renewal application. We will address these issues with the following specific
aims: SA 1: Determine how precisely timed Treg-depletion and CTLA-4 blockade impacts malaria-specific T
cell and B cell responses to facilitate clearance of PRIMARY blood-stage infections. SA 2: Determine how
precisely timed Treg-depletion and/or CTLA-4 blockade impacts malaria-specific memory T cell and B cell
responses to facilitate species transcending control of SECONDARY blood-stage infections. SA 3: Dissect
how and when inhibitory pathways and cells limit clearance of PRIMARY infection and prevent development of
species transcending control of SECONDARY infections.

## Key facts

- **NIH application ID:** 9961472
- **Project number:** 5R01AI100527-08
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** John T Harty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,940
- **Award type:** 5
- **Project period:** 2012-05-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961472

## Citation

> US National Institutes of Health, RePORTER application 9961472, Understanding immune regulation in blood-stage malaria (5R01AI100527-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9961472. Licensed CC0.

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