Neutrophil Extracellular Traps Open the Pandora’s Box in Severe Malaria

Malaria is transmitted by mosquitoes and kills 2,000 humans in sub-Saharan Africa each day (1). Most of the victims are children younger than 5 years of age. Out of the five plasmodium species causing malaria, Plasmodium falciparum is responsible for most of the severe and fatal infections (2). Upon feeding, the female Anopheles mosquito inoculates sporozoites that seek out the hosts’ liver within minutes. After a first replication cycle in hepatocytes for 5–8 days, rupture releases the parasite into circulation where erythrocytes are infected. During the second replication cycle plasmodium consumes the contents and energy reserves of the erythrocytes, changes the membrane to enable adherence to the vessel walls (3), and produces waste, including crystalline urate (MSU) and hemozoin (4). After 24, 48, or 72 h, depending on the species, the infected erythrocytes synchronously burst and release their content into the circulation and cause first clinical symptoms (Figure 1). The key pathogenic processes that cause severe malaria include rapid increase of infected erythrocytes, destruction of both infected and uninfected erythrocytes, acute inflammation, and microvascular obstruction. The final outcome is a reduced tissue perfusion that leads to downstream events compromising the cellular metabolism (5). We hypothesize that intravascular formation of neutrophil extracellular traps (NETs) contributes to the vasculopathy, driving severe malaria. NETs are web-like structures of highly modified chromatin and antimicrobial peptides released by activated neutrophils (6). In this article, we discuss the evidence supporting the role of NET formation in the pathogenesis of malaria and propose potential therapeutic interventions.