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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.
AuthorsSamuel Rommelaere, Virginie Millet, Pascal Rihet, Scott Atwell, Emmanuèle Helfer, Lionel Chasson, Carole Beaumont, Giovanna Chimini, Maria do Rosário Sambo, Annie Viallat, Carlos Penha-Gonçalves, Franck Galland, Philippe Naquet
JournalThe American journal of pathology (Am J Pathol) Vol. 185 Issue 11 Pg. 3039-52 (Nov 2015) ISSN: 1525-2191 [Electronic] United States
PMID26343328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • GPI-Linked Proteins
  • Amidohydrolases
  • pantetheinase
Topics
  • Adolescent
  • Adult
  • Amidohydrolases (blood, metabolism)
  • Anemia
  • Animals
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Disease Susceptibility
  • Erythrocytes (physiology)
  • Female
  • GPI-Linked Proteins (blood, metabolism)
  • Homeostasis
  • Humans
  • Infant
  • Malaria (physiopathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress
  • Young Adult

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