<i>Plasmodium falciparum</i> infection induces T cell tolerance that is associated with decreased disease severity upon re-infection
Immunity to severe malaria is acquired quickly, operates independently of pathogen load, and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance remains unknown. We used a human rechallenge model of falciparum malaria in which healthy adult volunteers were infected three times over a 12 mo period to track the development of disease tolerance in real-time. We found that parasitemia triggered a hardwired innate immune response that led to systemic inflammation, pyrexia, and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, a single infection was sufficient to reprogram T cell activation and reduce the number and diversity of effector cells upon rechallenge. Crucially, this did not silence stem-like memory cells but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerized hosts were thus able to prevent collateral tissue damage in the absence of antiparasite immunity.
Authors
- Adam Harding (ORCID: https://orcid.org/0000-0003-1479-959X)
- Giorgio Napolitani (ORCID: https://orcid.org/0000-0002-3605-6394)
- Graeme Cowan (ORCID: https://orcid.org/0000-0002-1949-4253)
- Jordan R. Barrett (ORCID: https://orcid.org/0000-0003-0746-1945)
- Philip J. Spence (ORCID: https://orcid.org/0000-0002-5506-2773)
- Diana Mūnoz Sandoval (ORCID: https://orcid.org/0000-0001-8350-3989)
- Florian A. Bach (ORCID: https://orcid.org/0000-0002-0126-5516)
- Wiebke Nahrendorf (ORCID: https://orcid.org/0000-0002-4503-8761)
- Simon J. Draper (ORCID: https://orcid.org/0000-0002-9415-1357)
- Alasdair Ivens (ORCID: https://orcid.org/0000-0002-0112-3876)
- Michalina Mazurczyk (ORCID: https://orcid.org/0000-0001-7727-9036)
- Angela M. Minassian (ORCID: https://orcid.org/0000-0001-7832-9824)
- Sarah E. Silk (ORCID: https://orcid.org/0000-0003-0563-4814)
- Nick J. Edwards (ORCID: https://orcid.org/0000-0002-7030-7839)
- Nicholas J. Savill (ORCID: https://orcid.org/0000-0002-9769-6168)
- Natasha L. Smith (ORCID: https://orcid.org/0000-0003-0137-3143)
- Yrene Themistocleous (ORCID: https://orcid.org/0000-0001-9285-6639)
Institutions
- University of Oxford (GB)
- Oxford Biomedical Research (US)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Centre for Immunity, Infection and Evolution (GB)
- Institute of Immunology (HR)
- Oxford BioMedica (United Kingdom) (GB)
- Jenner Institute (GB)
- Universidad San Francisco de Quito (EC)
- University of Edinburgh (GB)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1084/jem.20241667
- Citations
- 4
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- United States Agency for International Development
- Wellcome Trust
- Global Challenges Research Fund
- Royal Society
- European Commission
- University of Edinburgh
- Darwin Trust of Edinburgh
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- NIHR Oxford Biomedical Research Centre