Renal control of disease tolerance to malaria

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Significance

Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality, claiming the lives of over ∼4.5 × 10 ⁵ individuals per year. Paradoxically, however, up to 98% of infected individuals survive the infection, establishing disease tolerance to malaria. We found that this host defense strategy, which does not target Plasmodium directly, relies on the capacity of renal proximal tubule epithelial cells to detoxify labile heme, a pathologic by-product of hemolysis that accumulates in plasma and urine during the blood stage of infection. This defense strategy prevents the onset of acute kidney injury, a clinical hallmark of severe malaria.

Abstract

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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Most cited references 25

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Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene.

J. Alam, D. Stewart, C Touchard … (1999)

Stress response elements, which mediate induction of the mouse heme oxygenase-1 (HO-1) gene by several agents, resemble the binding site for the activator protein-1 (Jun/Fos), Maf, and Cap'n'Collar/basic leucine zipper (CNC-bZIP) families of proteins. In L929 fibroblasts, significant activation of an HO-1 enhancer-reporter fusion gene was observed only with the CNC-bZIP class of proteins with Nrf2 exhibiting the highest level of trans-activation, between 25- and 30-fold. To further examine the role of this factor in HO-1 gene regulation, a dominant-negative mutant, Nrf2M, was generated and conditionally expressed in L929 cells. The mutant protein was detected in cytoplasmic and nuclear fractions but did not affect cell growth. Under conditions of Nrf2M overexpression, HO-1 mRNA accumulation in response to heme, cadmium, zinc, arsenite, and tert-butylhydroquinone was inhibited by 85-95%. In contrast, overexpression of a dominant-negative mutant of c-Jun decreased L929 cell growth but did not inhibit HO-1 gene activation. Nrf2 does not homodimerize, but CNC-bZIP.small Maf protein heterodimers and Nrf2. Jun protein complexes are proposed to function as trans-activators. Co-expression of Jun proteins or p18, however, had no significant affect or inhibited Nrf2-mediated trans-activation. Taken together, these results implicate Nrf2 in the induction of the HO-1 gene but suggest that the Nrf2 partner in this function is a factor other than p18 or Jun proteins.

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Ferritin: a cytoprotective antioxidant strategem of endothelium.

G. Nguemba Balla, William Rosenberg, F S Apple … (1992)

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.

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Hemoglobin metabolism in the malaria parasite Plasmodium falciparum.

S Francis, D. J. Sullivan, D Goldberg (1997)

Hemoglobin degradation in intraerythrocytic malaria parasites is a vast process that occurs in an acidic digestive vacuole. Proteases that participate in this catabolic pathway have been defined. Studies of protease biosynthesis have revealed unusual targeting and activation mechanisms. Oxygen radicals and heme are released during proteolysis and must be detoxified by dismutation and polymerization, respectively. The quinoline antimalarials appear to act by preventing sequestration of this toxic heme. Understanding the disposition of hemoglobin has allowed identification of essential processes and metabolic weakpoints that can be exploited to combat this scourge of mankind.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 19 March 2019

Publication date (Electronic): 4 March 2019

Publication date PMC-release: 4 March 2019

Volume: 116

Issue: 12

Pages: 5681-5686

Affiliations

[1] ^aInstituto Gulbenkian de Ciência , 2780-156 Oeiras, Portugal;

[2] ^bFaculty of Medicine, Department of Internal Medicine, University of Debrecen , H-4032, Debrecen, Hungary;

[3] ^cDepartment of Microbiology and Immunology, Stanford University , Stanford, CA 94305-5124;

[4] ^dDepartment of Medicine, Division of Nephrology, University of Alabama, Birmingham , AL 35294;

[5] ^eBirmingham Veterans Administration Medical Center , Birmingham, AL 35294

Author notes

⁷To whom correspondence should be addressed. Email: mpsoares@ 123456igc.gulbenkian.pt .

Edited by Peter Agre, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, and approved February 8, 2019 (received for review January 3, 2019)

Author contributions: S. Ramos, A.R.C., V.J., R.G., and M.P.S. designed research; S. Ramos, A.R.C., B.S., V.J., A.R., R.G., C.B., E.G., F.B., R.M., T.W.A., B.B., Z.G., P.F., D.T., S.C., S. Rebelo, and L.d.B. performed research; A.Z., S.B., and A.A. contributed new reagents/analytic tools; S. Ramos, A.R.C., B.S., V.J., A.R., R.G., C.B., E.G., F.B., R.M., T.W.A., B.B., Z.G., P.F., D.T., S.C., S. Rebelo, and M.P.S. analyzed data; and S. Ramos and M.P.S. wrote the paper.

¹A.R.C., B.S., and V.J. contributed equally to this work.

²Present address: Institute of Molecular Medicine, Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University, 40225 Dusseldorf, Germany.

³Present address: Department of Animal and Avian Sciences, University of Maryland at College Park, MD 20742-2311.

⁴Present address: Chronic Diseases Research Center, NOVA Medical School, 1150-082 Lisbon, Portugal.

⁵Present address: Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.

⁶Present address: Institute Curie, UMR144, 75000 Paris, France.

Author information

Viktoria Jeney http://orcid.org/0000-0003-4942-7091

Miguel P. Soares http://orcid.org/0000-0002-9314-4833

Article

Publisher ID: 201822024

DOI: 10.1073/pnas.1822024116

PMC ID: 6431151

PubMed ID: 30833408

SO-VID: e0955b70-a49d-4f8c-9598-9a93f566a648

License:

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).