Abstract
Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits—including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia—are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a “natural experiment” to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the “Gordian knot” of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.
Highlights
In the 4th century BC, Alexander the Great conquered the known Western world [1]
We propose that hemoglobinopathies slice the Gordian knot of falciparum malaria pathogenesis to protect children from the severe, life-threatening manifestations of the disease
Heterozygous hemoglobin S (HbAS, or sickle-cell trait) and homozygous hemoglobin C (HbCC, or hemoglobin C disease) reduce the risk of severe falciparum malaria in sub-Saharan African children by 90% and 70%, respectively [8]. These structural hemoglobin variants do not protect from P. falciparum infection [8], suggesting they interfere with the specific molecular mechanisms responsible for the morbidity of falciparum malaria
Summary
In the 4th century BC, Alexander the Great conquered the known Western world [1]. Prior to his conquests in Asia, he encountered the Gordian knot, a complex knot of bark affixing a mythic ox-cart to a post in the town of Gordium. As one of history’s greatest military commanders, Alexander subsequently assembled and ruled an empire stretching from the Eastern Mediterranean to the Himalayas while remaining undefeated in battle These military conquests were presaged by his ‘‘Alexandrian solution’’ to the Gordian knot, demonstrating decisiveness and imagination in the face of a complex and seemingly unsolvable problem. Heterozygous hemoglobin S (HbAS, or sickle-cell trait) and homozygous hemoglobin C (HbCC, or hemoglobin C disease) reduce the risk of severe falciparum malaria in sub-Saharan African children by 90% and 70%, respectively [8] These structural hemoglobin variants do not protect from P. falciparum infection [8], suggesting they interfere with the specific molecular mechanisms responsible for the morbidity of falciparum malaria. We review the proposed mechanisms by which hemoglobinopathies (and fetal hemoglobin) protect against falciparum malaria
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