Targeting circulating labile heme as a defense strategy against malaria

Area of Science:

• Malariology
• Hematology
• Pathogenesis of infectious diseases

Background:

• Severe malaria involves red blood cell lysis and release of extracellular hemoglobin (HB) and labile heme.
• Heme scavenging proteins, haptoglobin (HP) and hemopexin (HPX), may counteract malaria pathogenesis.

Purpose of the Study:

• To investigate the role of HP and HPX in preventing severe malaria presentations.
• To determine if extracellular HB and labile heme scavenging by HP and HPX mitigate malaria pathogenesis.

Main Methods:

• Assessed circulating labile heme, HP, and HPX levels in children with severe Plasmodium falciparum malaria.
• Utilized genetic Hp and/or Hpx deletion in mice infected with Plasmodium.
• Correlated heme and HPX levels with serological markers of acute kidney injury (AKI).

Main Results:

• Circulating labile heme is an independent risk factor for severe P. falciparum malaria in children.
• HP and HPX levels were negatively correlated with labile heme but were not risk factors themselves.
• Hp/Hpx deletion in mice led to heme accumulation, increased mortality, and AKI in aging, but not adult, infected mice.

Conclusions:

• HP and HPX play an age-dependent role in preventing severe malaria pathogenesis.
• Heme scavenging by HP and HPX is crucial for mitigating malaria-associated pathology, particularly in aging individuals.
• These findings suggest potential therapeutic strategies targeting heme toxicity in severe malaria.