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 global cause of morbidity and mortality among children residing in Plasmodium falciparum transmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreased HSPA1A, a heat shock protein 70 (Hsp70) coding gene. Hsp70 is a ubiquitous chaperone that regulates nuclear factor-kappa B (NF-κB) signaling and production of proinflammatory cytokines known to be important in malaria pathogenesis (for example, 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 leukocytic HSP70 transcripts were reduced in SMA relative to nonsevere malaria, and that intraleukocytic hemozoin (PfHz) was associated with lower HSP70. HSP70 was correlated with reticulocyte production and Hb. Since glutamine (Gln) upregulates Hsp70, modulates NF-κB activation and attenuates overexpression of proinflammatory 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) with PfHz caused a time-dependent decrease in Hsp70 transcripts/protein and NF-κB activation. Gln treatment of PBMCs overcame PfHz-induced suppression of HSP70 transcripts/protein, reduced NF-κB activation and suppressed overexpression of IL-1β, IL-6 and TNF-α. These findings demonstrate that SMA is characterized by reduced intraleukocytic HSP70 and circulating Gln, and that PfHz-induced suppression of HSP70 can be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.

Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling

“…Binding of C1q to LAIR1 inhibits cellular activation and prevents the production of cytokines containing NF-κB and IRAF promoter response elements [41]. Our previous studies demonstrate that treatment of PBMCs with Pf Hz induces NF-κB activation and cytokine production [42]. Since phagocytosis of Pf Hz decreased LAIR1 transcription in cultured PBMCs, and blocked the induction of pLAIR1 by C1q, we determined the effect of C1q on pNF-κB p65 in Pf Hz-treated cells.…”

Distinct amino acid and lipid perturbations characterize acute versus chronic malaria

“…Still, preclinical testing will be required to explore the possible benefits of such interventions, as the complexity of host-parasite interactions makes the outcomes and possible unexpected adverse consequences difficult to predict (59). For example, iron supplementation administered in a clinical trial for malarial anemia resulted in increased mortality (59), and elevated plasma glutamine has been associated with both better outcomes in the context of malarial anemia (60) and poor outcomes in the context of cerebral malaria (61). LysoPC administration, which is currently under investigation as an adjunctive therapy for sepsis (62), may prove useful in malaria for both treating acute disease and reducing transmissibility (58).…”

Insights into malaria pathogenesis gained from host metabolomics

“…https://doi.org/10.1371/journal.ppat.1008930.g001 glutamine levels are depleted in the human host in both falciparum and vivax malaria [9,21,22,28]. In addition to impacting arginine biosynthesis ( Fig 1A), low plasma glutamine has been associated with severe malarial anemia in children with P. falciparum [29] and with impaired humoral immunity in a murine model of severe malaria [27]. Conversely though, inhibiting glutamine metabolism is associated with increased survival in a murine model of late stage cerebral malaria (CM) via reducing immune-mediated pathology in the brain [30].…”

“…Studies comparing the metabolome of malaria with non-malarial febrile illnesses have identified both common and distinct features of malaria [ 9 , 52 ]. RDTs that include both Plasmodium infection markers (e.g., elevated pipecolic acid [ 45 ] and pinene [ 46 ]) and disease severity markers (e.g., depleted arginine [ 16 ], glutamine [ 29 ], and citrulline [ 17 ]) could have diagnostic and prognostic benefit.…”