Renal control of disease tolerance to malaria

Abstract

Malaria, the disease caused byPlasmodiumspp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that killPlasmodium. 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 targetPlasmodiumdirectly. 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 ofPlasmodiuminfection, 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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“…Proximal tubules within the organoids were able to carry out endocytosis, as evidence of functional maturity [99]. Kidney organoids can be used as a platform to develop new drugs to treat chronic kidney disease [113].…”

Die zelluläre Basis des Organversagens bei Sepsis – Signalwege in Gewebeschädigung und Reparaturprozessen

“…As a prototypical example accumulation of labile heme in plasma and urine during Plasmodium infection has been shown to induce pronounced disease tolerance to malaria. Specifically, the heme-induced tolerance response prevents the development of acute kidney injury, a clinical hallmark of severe malaria [34]. How do parenchymal organs cope with resistance and tolerance responses of the immune system?…”