Serum Pantetheinase/Vanin Levels Regulate Erythrocyte Homeostasis and Severity of Malaria

Abstract

Tissue pantetheinase, encoded by the VNN1 gene, regulates response to stress, and previous studies have shown that VNN genes contribute to the susceptibility to malaria. Herein, we evaluated the role of pantetheinase on erythrocyte homeostasis and on the development of malaria in patients and in a new mouse model of pantetheinase insufficiency. Patients with cerebral malaria have significantly reduced levels of serum pantetheinase activity (PA). In mouse, we show that a reduction in serum PA predisposes to severe malaria, including cerebral malaria and severe anemia. Therefore, scoring pantetheinase in serum may serve as a severity marker in malaria infection. This disease triggers an acute stress in erythrocytes, which enhances cytoadherence and hemolysis. We speculated that serum pantetheinase might contribute to erythrocyte resistance to stress under homeostatic conditions. We show that mutant mice with a reduced serum PA are anemic and prone to phenylhydrazine-induced anemia. A cytofluorometric and spectroscopic analysis documented an increased frequency of erythrocytes with an autofluorescent aging phenotype. This is associated with an enhanced oxidative stress and shear stress-induced hemolysis. Red blood cell transfer and bone marrow chimera experiments show that the aging phenotype is not cell intrinsic but conferred by the environment, leading to a shortening of red blood cell half-life. Therefore, serum pantetheinase level regulates erythrocyte life span and modulates the risk of developing complicated malaria.

The Pathophysiological Role of CoA

“…VNN3 is found in various tissues, and this isoform is not attached to membranes, and its expression is upregulated in the inflammatory state or during oxidative stress. Together VNN1 and VNN3 contribute to extracellular pantetheine degradation [44,49].…”

“…Lower activity of pantetheinase leads to lower levels of anti-plasmodial cysteamine [148]. Moreover, a reduced level of serum pantetheinase activity predisposes patients to severe and complicated forms of malaria, including cerebral malaria and severe anemia, due to the diminished half-life of erythrocytes [49]. These findings seem to argue that the parasite depends on the host supply of Pan; therefore, a lower level of Pan would not be expected to benefit to Plasmodium.…”

Proteomic Analysis of Non-depleted Serum Proteins from Bottlenose Dolphins Uncovers a High Vanin-1 Phenotype

“…Furthermore, popular rodent models of duodenal ulcers are created through the administration of cysteamine 54 55 . On the other hand, Vanin-1 confers a protective phenotype to pancreatic beta islet cells 56 , hepatotoxic liver injury 57 , and red blood cells 58 while cysteamine administration has been shown to reduce renal fibrosis 59 , renal cystinosis 60 , and neurodegenerative disorders 61 .…”

A NIR fluorescent probe for Vanin-1 and its applications in imaging, kidney injury diagnosis, and the development of inhibitor

“…Importantly, Vanin-1 plays a vital role in multiple physiological and biological processes ranging from gluconeogenesis, pantothenic acid recycling, and cell migration, as well as oxidative stress regulation and inflammation aggregation in various pathological status 3 , 4 , 5 , 6 , 7 . It has a wide expression in different organs, especially in kidney and intestine 8 , 9 , 10 . Recent studies reveal that Vanin-1 expression is tightly intertwined with occurrence and development of certain diseases, such as kidney injury, hepatotoxicity, inflammatory bowel disease (IBD), diabetes and malaria 8 , 10 .…”

“…It has a wide expression in different organs, especially in kidney and intestine 8 , 9 , 10 . Recent studies reveal that Vanin-1 expression is tightly intertwined with occurrence and development of certain diseases, such as kidney injury, hepatotoxicity, inflammatory bowel disease (IBD), diabetes and malaria 8 , 10 . In view of the powerful functions of Vanin-1 and growing body of evidence, urinary Vanin-1 is regarded as a predictive biomarker for various kidney diseases, including drug-induced renal injury, acute kidney injury and diabetic nephropathy 11 , 12 , 13 .…”