title: Malaria induces anemia through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen.
abstract: Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected erythrocytes and is a frequent fatal complication. It is proportional not to circulating parasitemia but total parasite mass (sequestered) in the organs. Thus, immune responses that clear parasites in organs may trigger changes leading to anemia. Here, we use an outbred-rat model where increasing parasite removal in the spleen escalated uninfected-erythrocyte removal. Splenic parasite clearance was associated with activated CD8(+) T cells, immunodepletion of which prevented parasite clearance. CD8(+) T cell repletion and concomitant reduction of the parasite load was associated with exacerbated (40 to 60%) hemoglobin loss and changes in properties of uninfected erythrocytes. Together, these data suggest that CD8(+) T cell-dependent parasite clearance causes erythrocyte removal in the spleen and thus anemia. In children infected with the human malaria parasite Plasmodium falciparum, elevation of parasite biomass (not the number of circulating parasites) increased the odds ratio for SMA by 3.5-fold (95% confidence intervals [CI95%], 1.8- to 7.5-fold). CD8(+) T cell expansion/activation independently increased the odds ratio by 2.4-fold (CI95%, 1.0- to 5.7-fold). Concomitant increases in both conferred a 7-fold (CI95%, 1.9- to 27.4-fold)-greater risk for SMA. Together, these data suggest that CD8(+)-dependent parasite clearance may predispose individuals to uninfected-erythrocyte loss and SMA, thus informing severe disease diagnosis and strategies for vaccine development.
  
  
  OBJECTIVE
  Malaria is a major global health problem. Severe malaria anemia (SMA) is a complex disease associated with partial immunity. Rapid hemoglobin reductions of 20 to 50% are commonly observed and must be rescued by transfusion (which can carry a risk of HIV acquisition). The causes and risk factors of SMA remain poorly understood. Recent studies suggest that SMA is linked to parasite biomass sequestered in organs. This led us to investigate whether immune mechanisms that clear parasites in organs trigger anemia. In rats, erythropoiesis is largely restricted to the bone marrow, and critical aspects of the spleen expected to be important in anemia are similar to those in humans. Therefore, using a rat model, we show that severe anemia is caused through CD8(+) T cell-dependent parasite clearance and erythrocyte removal in the spleen. CD8 activation may also be a new risk factor for SMA in African children.
authors.forename: Innocent
authors.initials: I
authors.lastname: Safeukui
authors.forename: Noé D
authors.initials: ND
authors.lastname: Gomez
authors.forename: Aanuoluwa A
authors.initials: AA
authors.lastname: Adelani
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Florence
authors.initials: F
authors.lastname: Burte
authors.affiliation: Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Oyo, Nigeria.
authors.forename: Nathaniel K
authors.initials: NK
authors.lastname: Afolabi
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Akondy
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, Indiana, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Velazquez
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Anthony
authors.identifier: http://orcid.org/0000-0002-8490-6058
authors.initials: A
authors.lastname: Holder
authors.affiliation: Centre for Genetics and Genomics, School of Biology, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Rita
authors.initials: R
authors.lastname: Tewari
authors.affiliation: INSERM-UPMC (Paris 6 University), Unité Mixte de Recherche s945, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Buffet
authors.affiliation: Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Oyo, Nigeria.
authors.forename: Biobele J
authors.initials: BJ
authors.lastname: Brown
authors.affiliation: Childhood Malaria Research Group, University College Hospital, Ibadan, Nigeria.
authors.forename: Wuraola A
authors.initials: WA
authors.lastname: Shokunbi
authors.affiliation: Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: David
authors.initials: D
authors.lastname: Olaleye
authors.forename: Olugbemiro
authors.initials: O
authors.lastname: Sodeinde
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kazura
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Red Cell Physiology Laboratory, New York Blood Center, New York, New York, USA.
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Delmiro
authors.initials: D
authors.lastname: Fernandez-Reyes
authors.affiliation: khaldar@nd.edu.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Haldar
mesh_terms: D000740:Anemia / Q000209:etiology / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism / Q000469:parasitology; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000150:complications* / Q000276:immunology / Q000469:parasitology; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000502:physiology*; D051381:Rats; D013154:Spleen / Q000276:immunology* / Q000469:parasitology
chemical_list: D006454:Hemoglobins