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Infection and Immunity, September 2009, p. 3864-3871, Vol. 77, No. 9
0019-9567/09/$08.00+0 doi:10.1128/IAI.00342-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Suppression of a Novel Hematopoietic Mediator in Children with Severe Malarial Anemia
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Christopher C. Keller,1,2,
Collins Ouma,3,4,
Yamo Ouma,3
Gordon A. Awandare,1,5
Gregory C. Davenport,1,6
Tom Were,3
James B. Hittner,7
John M. Vulule,8
John M. Ong'echa,3,6 and
Douglas J. Perkins3,6*
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania,1 Laboratory of Human Pathogens, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania,2 University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya,3 Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya,4 Department of Biochemistry, University of Ghana, Legon, Accra, Ghana,5 Global and Geographic Medicine Program, Division of Infectious Diseases, University of New Mexico School of Medicine, Albuquerque, New Mexico,6 Department of Psychology, College of Charleston, Charleston, South Carolina,7 Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya8
Received 25 March 2009/ Returned for modification 7 May 2009/ Accepted 1 June 2009
In areas of holoendemic Plasmodium falciparum transmission, severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality. Although many soluble mediators regulate erythropoiesis, it is unclear how these factors contribute to development of SMA. Investigation of novel genes dysregulated in response to malarial pigment (hemozoin [PfHz]) revealed that stem cell growth factor (SCGF; also called C-type lectin domain family member 11A [CLEC11A]), a hematopoietic growth factor important for development of erythroid and myeloid progenitors, was one of the most differentially expressed genes. Additional experiments with cultured peripheral blood mononuclear cells (PBMCs) demonstrated that PfHz decreased SCGF/CLEC11A transcriptional expression in a time-dependent manner. Circulating SCGF levels were then determined for Kenyan children (n = 90; aged 3 to 36 months) presenting at a rural hospital with various severities of malarial anemia. SCGF levels in circulation (P = 0.001) and in cultured PBMCs (P = 0.004) were suppressed in children with SMA. Circulating SCGF also correlated positively with hemoglobin levels (r = 0.241; P = 0.022) and the reticulocyte production index (RPI) (r = 0.280; P = 0.029). In addition, SCGF was decreased in children with reduced erythropoiesis (RPI of <2) (P < 0.001) and in children with elevated levels of naturally acquired monocytic PfHz (P = 0.019). Thus, phagocytosis of PfHz promotes a decrease in SCGF gene products, which may contribute to reduced erythropoiesis in children with SMA.
* Corresponding author. Mailing address: Global and Geographic Medicine Program, University of New Mexico, Division of Infectious Diseases, MSC10-5550, 1 University of New Mexico, Albuquerque, NM 87131-0001. Phone: (505) 272-6867. Fax: (505) 272-8441. E-mail: dperkins{at}salud.unm.edu
Published ahead of print on 15 June 2009.
Supplemental material for this article may be found at http://iai.asm.org/.
C.C.K. and C.O. contributed equally to this study.
Infection and Immunity, September 2009, p. 3864-3871, Vol. 77, No. 9
0019-9567/09/$08.00+0 doi:10.1128/IAI.00342-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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