Plasmodium Strain Determines Dendritic Cell Function Essential for Survival from Malaria

Abstract

The severity of malaria can range from asymptomatic to lethal infections involving severe anaemia and cerebral disease. However, the molecular and cellular factors responsible for these differences in disease severity are poorly understood. Identifying the factors that mediate virulence will contribute to developing antiparasitic immune responses. Since immunity is initiated by dendritic cells (DCs), we compared their phenotype and function following infection with either a nonlethal or lethal strain of the rodent parasite, Plasmodium yoelii, to identify their contribution to disease severity. DCs from nonlethal infections were fully functional and capable of secreting cytokines and stimulating T cells. In contrast, DCs from lethal infections were not functional. We then transferred DCs from mice with nonlethal infections to mice given lethal infections and showed that these DCs mediated control of parasitemia and survival. IL-12 was necessary for survival. To our knowledge, our studies have shown for the first time that during a malaria infection, DC function is essential for survival. More importantly, the functions of these DCs are determined by the strain of parasite. Our studies may explain, in part, why natural malaria infections may have different outcomes.

Author Summary

Malaria is a complex disease and there is little data on why Plasmodium infections have different outcomes that can range from asymptomatic to lethal infections. Since immunity is initiated by dendritic cells (DCs), several studies have investigated DC function during malaria. Current data on the effects of infection on DC functions are inconclusive, with one school of thought being that DC function is normal and the other that DC function is compromised. However, these studies have used different species and strains of Plasmodium. We have compared DC function during a lethal and nonlethal infection and found significant differences. Our study shows that the strain of parasite determines if DCs remain functional following infection. Moreover, by transferring DCs between mice, we show that DC function is essential for survival from a lethal infection. This study offers some insight into the current controversy and offers a plausible explanation for differences in the severity of disease.