Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 12, Pages 5681-5686Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1822024116
Keywords
infection; malaria; disease tolerance; heme; kidney
Categories
Funding
- Fundacao para a Ciencia e Tecnologia [PTDC/SAU-TOX/116627/2010, HMSP-ICT/0018/2011, LISBOA-01-0145-FEDER-029411, SFRH/BPD/101608/2014, SFRH/BD/51877/2012]
- Fundacao Calouste Gulbenkian [217/BD/17]
- European Union [ERC-2011-AdG 294709]
- Hungarian National Research, Development, and Innovation Office [K116024]
- Marie Sklodowska-Curie Research Fellowship [707998]
- European Molecular Biology Organization (EMBO) Long-Term Fellowship [ALTF290-2017]
- NIH [K01 DK103931, R01 DK059600, P30 DK079337]
- Marie Curie Actions (MSCA) [707998] Funding Source: Marie Curie Actions (MSCA)
- Fundação para a Ciência e a Tecnologia [SFRH/BD/51877/2012] Funding Source: FCT
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Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium. However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.
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