Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of Hemozoin in Suppressing Hsp70 and NF-κB activation.

Severe malarial anemia [SMA, hemoglobin (Hb) <5.0 g/dL] is a leading cause of global morbidity and mortality among children residing intransmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreased, 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 leukocytictranscripts were reduced in SMA relative to non-severe malaria, and that intraleukocytic hemozoin (Hz) was associated with lower.was 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) withHz caused a time-dependent decrease in Hsp70 transcripts/protein, and NF-κB activation. Gln treatment of PBMCs overcameHz-induced suppression oftranscripts/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 intraleukocyticand circulating Gln, and thatHz-induced suppression ofcan be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.