Serum pantetheinase/vanin levels regulate erythrocyte homeostasis and severity of malaria.
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.
Immunology Center of Marseille-Luminy, Aix Marseille Université (UM2), the National Institute of Health and Medical Research INSERM U1104, the Centre National de la Recherche Scientifique CNRS UMR7280, Marseille, France.
Samuel
S
Rommelaere
Immunology Center of Marseille-Luminy, Aix Marseille Université (UM2), the National Institute of Health and Medical Research INSERM U1104, the Centre National de la Recherche Scientifique CNRS UMR7280, Marseille, France.
Virginie
V
Millet
Technological Advances for Genomics and Clinics (TAGC), Aix-Marseille Université, UMR_S 1090, INSERM U1090, Marseille, France.
Pascal
P
Rihet
Marseilles Interdisciplinary Nanoscience Centre, Aix-Marseille Université, CNRS UMR7325, Marseille, France.
Scott
S
Atwell
Marseilles Interdisciplinary Nanoscience Centre, Aix-Marseille Université, CNRS UMR7325, Marseille, France.
Emmanuèle
E
Helfer
Immunology Center of Marseille-Luminy, Aix Marseille Université (UM2), the National Institute of Health and Medical Research INSERM U1104, the Centre National de la Recherche Scientifique CNRS UMR7280, Marseille, France.
Lionel
L
Chasson
Biomedical Research Center Bichat-Beaujon, Université Paris Diderot, INSERM U773, Paris, France.
Carole
C
Beaumont
Immunology Center of Marseille-Luminy, Aix Marseille Université (UM2), the National Institute of Health and Medical Research INSERM U1104, the Centre National de la Recherche Scientifique CNRS UMR7280, Marseille, France.
Giovanna
G
Chimini
Faculty of Medicine, Universidade Katyavala Bwila, Benguela, Angola.
Maria do Rosário
Mdo R
Sambo
Marseilles Interdisciplinary Nanoscience Centre, Aix-Marseille Université, CNRS UMR7325, Marseille, France.
Annie
A
Viallat
Gulbenkian Institute of Science, Oeiras, Portugal.
Carlos
C
Penha-Gonçalves
Immunology Center of Marseille-Luminy, Aix Marseille Université (UM2), the National Institute of Health and Medical Research INSERM U1104, the Centre National de la Recherche Scientifique CNRS UMR7280, Marseille, France. Electronic address: fgpn@ciml.univ-mrs.fr.
Franck
F
Galland
Immunology Center of Marseille-Luminy, Aix Marseille Université (UM2), the National Institute of Health and Medical Research INSERM U1104, the Centre National de la Recherche Scientifique CNRS UMR7280, Marseille, France. Electronic address: naquet@ciml.univ-mrs.fr.
Philippe
P
Naquet
D000293:Adolescent; D000328:Adult; D000581:Amidohydrolases / Q000097:blood* / Q000378:metabolism; D000740:Anemia; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000502:physiology*; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007223:Infant; D008288:Malaria / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D055815:Young Adult
D058851:GPI-Linked Proteins; D000581:Amidohydrolases; C022314:pantetheinase