A central role for free heme in the pathogenesis of severe malaria: the missing link?

Ferreira, Ana; Balla, József; Jeney, Viktória; Balla, György; Soares, Miguel P.

doi:10.1007/s00109-008-0368-5

Cited by 183 publications

(233 citation statements)

References 97 publications

Supporting

Mentioning

212

Contrasting

Unclassified

Order By: Relevance

“…The oxidative stress response orchestrated by the transcription factor, nuclear factor E2-related factor-2 (NRF2) 27,28 (Figure 2) can contribute critically to the establishment of disease tolerance to infection, as demonstrated for malaria 20,29 . Briefly, the blood stage of Plasmodium infection is associated with hemolysis and hence with generation of extracellular hemoglobin 20,21,29,30 . Upon oxidation, extracellular hemoglobin releases its prosthetic heme groups, which act as catalysts in the production of reactive oxygen species (ROS) and nitrogen species (RNS).…”

Section: Stress Responses In Tissue Damage Controlmentioning

confidence: 99%

“…Upon oxidation, extracellular hemoglobin releases its prosthetic heme groups, which act as catalysts in the production of reactive oxygen species (ROS) and nitrogen species (RNS). This can lead to oxidative stress and cellular damage in host parenchyma tissues 12,13,16,31 , driving the pathogenesis of severe forms of malaria 30 .…”

Section: Stress Responses In Tissue Damage Controlmentioning

confidence: 99%

See 1 more Smart Citation

Disease tolerance and immunity in host protection against infection

2017

Self Cite

View full text Add to dashboard Cite

The immune system has most likely evolved to limit the negative impact exerted by pathogens on host homeostasis. This defense strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defense strategy that limits the extent of dysfunction imposed to host parenchyma tissues during infection, without exerting a direct negative impact on pathogens.This defense strategy, called disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens, while uncoupling immunedriven resistance mechanisms from immunopathology and disease. Here we provide a unifying view of resistance and disease tolerance within the framework of immunity to infection.

show abstract

Section: Stress Responses In Tissue Damage Controlmentioning

confidence: 99%

Section: Stress Responses In Tissue Damage Controlmentioning

confidence: 99%

Disease tolerance and immunity in host protection against infection

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cell-free hemoglobin released during the blood stage of Plasmodium infection promotes tissue oxidation and organ failure [101]. Animal models have shown that HO-1, encoded by the stress-inducible gene Hmox1, can protect the tissues from the heme toxic effect independently of pathogen load [102].…”

Section: Induction Of Antioxidant Mechanismsmentioning

confidence: 99%

“…Animal models have shown that HO-1, encoded by the stress-inducible gene Hmox1, can protect the tissues from the heme toxic effect independently of pathogen load [102]. Such a mechanism could explain the protection mediated by sickle cell anemia [101]. …”

mentioning

confidence: 99%

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Galatas

Bassat

Mayor

2016

Trends in Parasitology

115

122

View full text Add to dashboard Cite

With malaria elimination back on the international agenda, programs face the challenge of targeting all Plasmodium infections, not only symptomatic cases. As asymptomatic individuals are unlikely to seek treatment, they are missed by passive surveillance while remaining infectious to mosquitoes, thus acting as silent reservoirs of transmission. To estimate the risk of asymptomatic infections in various phases of malaria elimination, we need a deeper understanding of the underlying mechanisms favoring carriage over disease, which may involve both pathogen and host factors. Here we review our current knowledge on the determinants leading to Plasmodium falciparum symptomless infections. Understanding the host-pathogen interactions that are most likely to affect transitions between malaria disease states could guide the development of tools to tackle asymptomatic carriers in elimination settings. Being AsymptomaticPeaceful coexistence with the infected host, rarely causing clinical symptoms, is a common but poorly understood phenomenon that occurs for many human pathogens [1]. Because such asymptomatic cases of infection occur without eventual overt symptoms, they do not come to clinical attention, thus representing a large hidden reservoir of active infection that permits their persistence and eventual spread to other human hosts. This is the case for many malaria infections in semi-immune individuals from endemic areas, which commonly cause a mild febrile illness or no apparent symptoms at all, while keeping parasite numbers at low densities [2] (Box 1).Carriage of asymptomatic malaria (see Glossary) infections, being at the same time difficult to detect and to manage, has considerable implications for the design and use of malaria elimination strategies. Symptomless infections that persist during the dry season in areas of seasonal transmission have been suggested to seed the malaria outbreaks after annual rains when mosquitoes reappear [3]. Similarly, asymptomatic parasitemia may potentially contribute to persistence of transmission in low-transmission settings [4]. However, the precise contribution of asymptomatic malaria to transmission in areas that have achieved substantial reductions in the malaria burden remains a matter of debate [5], as is the assumption that detecting and targeting these individuals for radical treatment, as opposed to using mass drug administration approaches, would be an efficient and effective tactic. Moreover, eradication in Europe, North America, and other parts of the world using no better diagnostics than microscopy [6] suggest that key determinants of success might not be finding the last parasite. From a practical point of view, the proportion of asymptomatic infections in certain situations and phases of malaria elimination may impose the need for modifications of detection methods (active versus passive case detection) [7] if, for example, symptom-based surveillance at health facilities is insufficient and mass blood surveys are necessary to inform the design of elimination i...

show abstract

“…Evidence from previous studies have shown that haem, the substrate of HO‐1, is also its major inducer 15, 16, 17, 20, 33, and when cells are exposed to haem there is an increased expression of HO‐1 to catabolize haem and prevent its cytotoxicity 33. As patients with the HbAS genotype have higher levels of haem compared with HbAA genotype at convalescence, we investigated the possibility of a corresponding induction of HO‐1 in both genotypes.…”

Section: Discussionmentioning

confidence: 99%

Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection

Ademolue

Amodu

Awandare

2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryThe controlled induction of haemoxygenase‐1 (HO‐1), an enzyme that catabolizes haem, has been shown to reduce haem, preventing pathologies associated with haem toxicity. The hemoglobin genotype HbAS confers reduced susceptibility to severe complications of malaria by a mechanism that is not well understood. Using a longitudinal approach, we investigated the effect of baseline concentrations of HO‐1 on the accumulation of haem during acute Plasmodium falciparum malaria in HbAS and HbAA genotypes. Plasma concentrations of haem, HO‐1 and cytokines were quantified in venous blood obtained from children (9 months–5 years of age) during malaria infection, and at convalescence (baseline levels). Parasitaemia was determined during malaria infection. In patients with the HbAA genotype, there was a significant elevation in the plasma concentration of haem (P = 0.002), and a consequent increased induction of HO‐1 (P < 0.001) during falciparum malaria compared with levels at convalescence. Contrary to HbAA, plasma concentration of haem did not change in the HbAS genotypical group (P = 0·110), and the induction of HO‐1 was reduced during malaria compared with levels at convalescence (P = 0·006). Higher plasma levels of haem were observed in HbAS compared with HbAA at convalescence (P = 0·010), but this difference did not affect the levels of HO‐1 within each genotype (P = 0·450). Relatively milder proinflammatory responses were observed in HbAS children during malaria infection compared to HbAA children. Our findings suggest that a mechanism of reduced susceptibility to severe malaria pathologies by the HbAS genotype may involve the control of haem, leading to controlled levels of HO‐1 and milder proinflammatory responses during acute malaria.

show abstract

A central role for free heme in the pathogenesis of severe malaria: the missing link?

Cited by 183 publications

References 97 publications

Disease tolerance and immunity in host protection against infection

Disease tolerance and immunity in host protection against infection

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection

Contact Info

Product

Resources

About