# Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

PROJECT SUMMARY
 The inability to acquire protective immunity against Plasmodium is a major obstacle to malaria
control. In the prior funding period, we showed that the Plasmodium orthologue of the host cytokine
macrophage migration inhibitory factor, termed PMIF, impairs germinal center formation and the
differentiation of T follicular helper cells (Tfh), leading to a reduction in the development of memory B and T
cells. We recapitulated genetic PMIF deficiency in a P. berghei strain by vaccination with a pmif RNA
replicon, which delayed blood-stage patency, augmented Tfh cell and germinal center responses, and
enhanced the differentiation of memory CD4 and liver-resident, circumsporozoite-specific CD8 T cells. We
observed improved control of infection and complete protection from re-infection, which was replicated by
adoptive transfer of CD8 or CD4 T cells from pmif RNA replicon immunized hosts. Our data indicate that
Plasmodium parasites utilize PMIF, which shows strict evolutionary conservation, to interfere with
immunologic memory. We propose the following Specific Aims to achieve our goal of better understanding
ineffective immunity to malaria and providing a foundation for better vaccines: Aim 1. Define the impact
and potential synergy of PMIF neutralization in the host response to circumsporozoite (CSP)
vaccination. The partial and waning immunity observed with the CSP-based RTS,S vaccine is due in part
to an inadequate memory T cell response. We hypothesize that combining CSP with PMIF vaccination will
increase T cell memory to CSP and provide optimal and high-level protection. We will study this approach
in collaboration with the Walter Reed Army Institute of Research by immunizing mice against PMIF
together with the Falciparum Malaria Vaccine-013 (FMP013) in a human CSP-transgenic P. berghei mouse
model. Aim 2. Define the impact of PMIF on Plasmodium liver-stage development. PMIF also
supports initial sporozoite infection and liver-stage parasite development by survival signaling through the
hepatocellular MIF receptor, CD74. We hypothesize that PMIF re-programs hepatocyte metabolism to
inhibit the host-protective apoptosis of infected hepatocytes. We will elucidate the pathways involved and
better define the impact of liver-stage PMIF expression on the developing immune response. Aim 3.
Evaluate the therapeutic potential of a novel small molecule PMIF inhibitor. We have developed a
first-in-class small molecule, 26k, that selectively blocks PMIF signaling through the host MIF receptor
CD74, reduces liver-stage parasite burden, and fully protects mice from cerebral malaria. We hypothesize
that pharmacologic PMIF antagonism with 26k may be a tractable approach for prophylaxis and liver-stage
treatment, and may augment immunologic memory responses. Closer knowledge of the PMIF pathway will
lead to better strategies for malaria therapy and vaccine development, and potentially may be generalized
to other parasites that express orthologous ...

## Key facts

- **NIH application ID:** 10149235
- **Project number:** 5R01AI110452-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** RICHARD J BUCALA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2014-04-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149235

## Citation

> US National Institutes of Health, RePORTER application 10149235, Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF (5R01AI110452-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149235. Licensed CC0.

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