title: Stage-dependent fate of Plasmodium falciparum-infected red blood cells in the spleen and sickle-cell trait-related protection against malaria.
abstract: BACKGROUND
  Sickle-cell trait (HbAS) reduces falciparum malaria risk and suppresses parasitaemia. Although several candidate mechanisms have been proposed, their epidemiological, clinical and experimental correlates have not been adequately explained. To explore the basis for generally lower parasitaemias and delayed malaria episodes in children with HbAS, it is hypothesized here that their spleen-dependent removal of ring-infected red blood cells (RBCs) is more efficient than in children with normal haemoglobin A (HbAA).
  
  
  METHODS
  The mechanical splenic retention of Plasmodium falciparum-infected RBCs from subjects with HbAS or HbAA was investigated using two physiologically relevant methods: microsphiltration and ex vivo spleen perfusion. P. falciparum-infected RBCs obtained from in vitro cultures and from patients were used in either normoxic or hypoxic conditions. The effect of sickling in ring-infected HbAS RBCs was also investigated.
  
  
  RESULTS
  When a laboratory-adapted parasite strain was analysed, ring-infected HbAA RBCs were retained in microsphilters at similar or greater levels than ring-infected HbAS RBCs, under normoxic (retention rate 62.5 vs 43.8 %, P < 0.01) and hypoxic (54.0 vs 38.0 %, P = 0.11) conditions. When parasitized RBCs from Malian children were analysed, retention of ring-infected HbAA and HbAS RBCs was similar when tested either directly ex vivo (32.1 vs 28.7 %, P = 0.52) or after one re-invasion in vitro (55.9 vs 43.7 %, P = 0.30). In hypoxia, sickling of uninfected and ring-infected HbAS RBCs (8.6 vs 5.7 %, P = 0.51), and retention of ring-infected HbAA and HbAS RBCs in microsphilters (72.5 vs 68.8 %, P = 0.38) and spleens (41.2 vs 30.4 %, P = 0.11), also did not differ. Retention of HbAS and HbAA RBCs infected with mature P. falciparum stages was greater than 95 %.
  
  
  CONCLUSIONS
  Sickle-cell trait is not associated with higher retention or sickling of ring-infected RBCs in experimental systems reflecting the mechanical sensing of RBCs by the human spleen. As observed with HbAA RBCs, HbAS RBCs infected with mature parasites are completely retained. Because the cytoadherence of HbAS RBCs infected with mature parasites is impaired, the very efficient splenic retention of such non-adherent infected RBCs is expected to result in a slower rise of P. falciparum parasitaemia in sickle-cell trait carriers.
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France.|Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odontostomatology, University of Bamako, Bamako, BP, 1805, Mali.|Laboratoire d'Excellence du Globule Rouge (GR-Ex), 75115, Paris, France.
authors.forename: Seidina A S
authors.initials: SA
authors.lastname: Diakité
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France.|Laboratoire d'Excellence du Globule Rouge (GR-Ex), 75115, Paris, France.
authors.forename: Papa Alioune
authors.initials: PA
authors.lastname: Ndour
authors.affiliation: Centre de Référence de la Drépanocytose, Hôpital Universitaire Necker Enfants Malades, 75012, Paris, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Brousse
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France.
authors.forename: Frederick
authors.initials: F
authors.lastname: Gay
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Roussel
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France.
authors.forename: Sylvestre
authors.initials: S
authors.lastname: Biligui
authors.affiliation: Laboratoire d'Excellence du Globule Rouge (GR-Ex), 75115, Paris, France.|INSERM U1163/CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Dussiot
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Prendki
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Lopera-Mesa
authors.affiliation: Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odontostomatology, University of Bamako, Bamako, BP, 1805, Mali.
authors.forename: Karim
authors.initials: K
authors.lastname: Traoré
authors.affiliation: Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odontostomatology, University of Bamako, Bamako, BP, 1805, Mali.
authors.forename: Drissa
authors.initials: D
authors.lastname: Konaté
authors.affiliation: Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odontostomatology, University of Bamako, Bamako, BP, 1805, Mali.
authors.forename: Saibou
authors.initials: S
authors.lastname: Doumbia
authors.affiliation: Department of Chirurgie Digestive et Viscérale, Hôpital Beaujon, AP-HP, 92110, Clichy, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cros
authors.affiliation: Department of Chirurgie Digestive et Viscérale, Hôpital Beaujon, AP-HP, 92110, Clichy, France.
authors.forename: Safi
authors.initials: S
authors.lastname: Dokmak
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odontostomatology, University of Bamako, Bamako, BP, 1805, Mali.
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakité
authors.affiliation: INSERM U1134, Paris 5, Paris 7, Institut National de la Transfusion Sanguine, 75015, Paris, France. pabuffet@gmail.com.|Laboratoire d'Excellence du Globule Rouge (GR-Ex), 75115, Paris, France. pabuffet@gmail.com.
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Buffet
keywords: Malaria; Plasmodium falciparum; Red blood cell; Retention; Sickle-cell trait; Spleen