Haemolysis and haem oxygenase-1 induction during persistent “asymptomatic” malaria infection in Burkinabé children

Abstract

BackgroundThe haemolysis associated with clinical episodes of malaria results in the liberation of haem, which activates the enzyme haem oxygenase-1 (HO-1). HO-1 has been shown to reduce neutrophil function and increase susceptibility to invasive bacterial disease. However, the majority of community-associated malaria infections are subclinical, often termed “asymptomatic” and the consequences of low-grade haemolysis during subclinical malaria infection are unknown.Study design and resultsAs part of an ongoing study of subclinical malaria in Burkina Faso, 23 children with subclinical Plasmodium falciparum infections (determined by qPCR) were compared with 21 village-matched uninfected control children. Infected children showed evidence of persistent haemolysis over 35 days, with raised plasma haem and HO-1 concentrations. Concentrations of IL-10, which can also directly activate HO-1, were also higher in infected children compared to uninfected children. Regression analysis revealed that HO-1 was associated with haemolysis, but not with parasite density, anaemia or IL-10 concentration.ConclusionsThis study reveals that subclinical P. falciparum malaria infection is associated with sustained haemolysis and the induction of HO-1. Given the association between HO-1, neutrophil dysfunction and increased risk of Salmonella bacteraemia, prolonged HO-1 induction may explain epidemiological associations and geographic overlap between malaria and invasive bacterial disease. Further studies are needed to understand the consequences of persistent subclinical malaria infection, low-grade haemolysis and raised HO-1 on immune cell function and risk of comorbidities.

Malaria, anemia, and invasive bacterial disease: A neutrophil problem?

“…One hypothesis, therefore, is that malaria‐induced neutrophil dysfunction results from hemolysis‐ and IL‐10‐driven HO‐1 induction. In support of this hypothesis, in a recent study of persistent malaria infections, we have found that heme drives inflammation, that parasite density and inflammation then drives IL‐10 production, and that heme and IL‐10 both then induce HO‐1 …”

“…However, the majority of malaria infections in the world are asymptomatic, with chronic, low‐density infections . As recent and low‐density malaria infections are a risk factor for NTS bacteremia, it is also important to understand if hemolysis, and resulting induction of HO‐1 and IL‐10, seen during these “asymptomatic” infections reaches the threshold needed for neutrophil dysfunction. In other words, in addition to defining the pathways leading to neutrophil dysfunction, we also need to identify the point at which the balance tips from these being host protective to increasing the risk to invasive NTS.…”

“…However, under conditions of hypoxia, oxidative stress, or infection (e.g., presence of LPS), the inducible isoform HO‐1 (encoded by heme oxygenase‐1 gene [ hmox1 ]) is upregulated to prevent heme‐induced pathology and ensure efficient iron recycling . Importantly, plasma heme and HO‐1 concentrations are raised during both acute and subclinical P. falciparum malaria infections in humans, and during acute P. yoelii infection in mice, competitive inhibition of HO‐1 enzyme activity restores the ability of P. yoelii ‐infected mice to control systemic NTS infections . Moreover, hmox1 induction increases NTS growth in murine macrophages, indicating that hemolysis (via heme and HO‐1) rather than malaria, per se, may be the true risk factor for invasive NTS disease in malaria patients.…”

“…In support of this hypothesis, in a recent study of persistent malaria infections, we have found that heme drives inflammation, that parasite density and inflammation then drives IL-10 production, and that heme and IL-10 both then induce HO-1. 73…”

Plasmodium Impairs Antibacterial Innate Immunity to Systemic Infections in Part Through Hemozoin-Bound Bioactive Molecules

“…Recent studies have characterized some of the underlying mechanisms by which Plasmodium infections increase susceptibility to invasive NTS infection (Cunnington et al, 2011(Cunnington et al, , 2012Lokken et al, 2014Lokken et al, , 2018Mooney et al, 2014Mooney et al, , 2018. First, Plasmodium-induced hemolysis results in the activation of heme oxygense-1 (HO-1), which mobilizes functionally immature granulocytes from the bone marrow.…”