Renal control of disease tolerance to malaria

Abstract

Malaria, the disease caused by <i>Plasmodium</i> spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill <i>Plasmodium</i> 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 <i>Plasmodium</i> 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 (<i>HMOX1</i>; HO-1) and ferritin H chain (<i>FTH</i>) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (<i>NRF2</i>). As it accumulates in plasma and urine during the blood stage of <i>Plasmodium</i> 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.