Malaria biology and disease pathogenesis: insights for new treatments

Abstract

Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast Asia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials, including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Our current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the high mortality of severe malaria. An understanding of the pathophysiology of severe disease may identify rational targets for drugs that improve survival.

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

“…Differences noted between Plasmodium falciparum strains and isolates in their maximum parasitemia [8], pyrogenic thresholds [9], multiplication rates [10], and cytoadhesion leading to sequestration in vital organs [11] suggest that there might be parasite factors that contribute to the development of asymptomatic infection.…”

“…PfEMP1s bind to several host receptors to mediate the sequestration of infected erythrocytes in vital organs [11] and drive inflammation by blocking the cytoprotective function of the endothelial protein C receptor [22]. PfEMP1s are encoded by approximately 60 var genes per parasite genome, which are expressed in a mutually exclusive manner to avoid simultaneous recognition by the immune system [11]. Host antibodies against PfEMP1 variants have been suggested to structure the switch between var genes in a hierarchical process [23], with parasites expressing conserved and virulent PfEMP1s eventually surpassed by less virulent and more diverse variants that dominate infections in semi-immune individuals.…”

“…Antibodies can also contribute to opsonin-mediated phagocytosis of infected erythrocytes and antibody-dependent cellular inhibition (ADCI). Finally, antibodies may also target PfEMP1s involved in parasite cytoadherence and rosetting, eventually preventing their sequestration in vital organs and leading to their clearance in the spleen [11,33,35].…”

“…Malaria is characterized by acute periodic febrile episodes triggered by the rupture of Plasmodium schizont stageinfected erythrocytes and the release of merozoites into the bloodstream [11]. This cyclical nature of the emergence of clinical symptoms is what led to the original nomenclature given to the fevers associated with malaria infections ('tertian' or 'quartan' fever) well before its life cycle was understood.…”

“…Antibodies can also contribute to opsonin-mediated phagocytosis of infected erythrocytes and antibody-dependent cellular inhibition (ADCI). Finally, antibodies may also target PfEMP1s involved in parasite cytoadherence and rosetting, eventually preventing their sequestration in vital organs and leading to their clearance in the spleen [11,33,35].Despite the apparent importance of antibodies, the role of antibody-mediated immunity for the transition between clinical disease and asymptomatic infection remains unclear. Several reports have shown antibody responses against Plasmodium merozoite antigens that predict a reduced risk of symptomatic malaria and high-density P. falciparum infections, including those against members of the serine-enriched repeat antigen (SERA) family [36], merozoite protein 4 (MSP-4) [36,37], MSP-1 19 [38], and apical merozoite antigen 1 (AMA-1) [39].…”