| Title: |
Plasmodium falciparum infection induces T cell tolerance that is associated with decreased disease severity upon re-infection |
| Authors: |
Muñoz Sandoval, Diana; Bach, Florian A.; Ivens, Alasdair; Harding, Adam C.; Smith, Natasha L.; Mazurczyk, Michalina; Themistocleous, Yrene; Edwards, Nick J.; Silk, Sarah E.; Barrett, Jordan R.; Cowan, Graeme J.M.; Napolitani, Giorgio; Savill, Nicholas J.; Draper, Simon J.; Minassian, Angela M.; Nahrendorf, Wiebke; Spence, Philip J. |
| Contributors: |
U.S. Agency for International Development; National Institute for Health Research Oxford Biomedical Research Centre; European Union’s Horizon 2020; Human Infection Challenge Network for Vaccine Development; Global Challenges Research Fund; Medical Research Council; Biotechnology and Biological Sciences Research Council; Darwin Trust of Edinburgh; Wellcome Trust; Royal Society; European Union; University of Edinburgh; Jenner Institute |
| Source: |
Journal of Experimental Medicine ; volume 222, issue 7 ; ISSN 0022-1007 1540-9538 |
| Publisher Information: |
Rockefeller University Press |
| Publication Year: |
2025 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1084/jem.20241667 |
| DOI: |
10.1084/jem.20241667/1942490/jem_20241667.pdf |
| Availability: |
https://doi.org/10.1084/jem.20241667; https://rupress.org/jem/article-pdf/doi/10.1084/jem.20241667/1942490/jem_20241667.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.FE7A88B3 |
| Database: |
BASE |