title: Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of Hemozoin in Suppressing Hsp70 and NF-κB activation.
abstract: Severe malarial anemia [SMA, hemoglobin (Hb) <5.0 g/dL] is a leading cause of global morbidity and mortality among children residing inPlasmodium falciparumtransmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreasedHSPA1A, a heat shock protein (Hsp) 70 coding gene. Hsp70 is a ubiquitous chaperone that regulates Nuclear Factor-kappa B (NF-κB) signaling and production of pro-inflammatory cytokines known to be important in malaria pathogenesis (e.g., IL-1β, IL-6 and TNF-α). Since the role of host Hsp70 in malaria pathogenesis is unexplored, we investigated Hsp70 and molecular pathways in children with SMA. Validation experiments revealed that leukocyticHSP70transcripts were reduced in SMA relative to non-severe malaria, and that intraleukocytic hemozoin (PfHz) was associated with lowerHSP70.HSP70was correlated with reticulocyte production and Hb. Since glutamine (Gln) up-regulates Hsp70, modulates NF-κB activation, and attenuates over-expression of pro-inflammatory cytokines, circulating Gln was measured in children with malaria. Reduced Gln was associated with increased risk of developing SMA. Treatment of cultured peripheral blood mononuclear cells (PBMCs) withPfHz caused a time-dependent decrease in Hsp70 transcripts/protein, and NF-κB activation. Gln treatment of PBMCs overcamePfHz-induced suppression ofHSP70transcripts/protein, reduced NF-κB activation, and suppressed over-expression of IL-1β, IL-6 and TNF-α. Findings here demonstrate that SMA is characterized by reduced intraleukocyticHSP70and circulating Gln, and thatPfHz-induced suppression ofHSP70can be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.
authors: Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Prakasha
authors: P
authors: Kempaiah
authors: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Karol
authors: K
authors: Dokladny
authors: Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Zachary
authors: Z
authors: Karim
authors: University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya.
authors: Evans
authors: E
authors: Raballah
authors: Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.|University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya.
authors: John M
authors: JM
authors: Ong'echa
authors: Departments of Medicine and Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
authors: Pope L
authors: PL
authors: Moseley
authors: Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.|University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya.
authors: Douglas J
authors: DJ
authors: Perkins
keywords: Glutamine; Hemozoin; Hsp70; NF-κB; anemia; inflammatory mediators