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.

Plasmodium Infection and Endotoxic Shock Induce the Expansion of Regulatory Dendritic Cells

“…In contrast, other groups have also documented seemingly opposite results, where the DC maturation response is modulated by Plasmodium, resulting in the inability to up-regulate costimulatory and histocompatibility molecules, secretion of anti-inflammatory mediators, and inhibition of T cell responses (5-13, 21). More recently, there has been a renewed attempt to understand these differences, looking at the time of infection (14, 18), CD11c high DC subpopulations (13,16,18), and the different Plasmodium species being used as model infections (13,21). In this study, we show that there are several factors that will dictate the phenotype of the DC population during a Plasmodium infection: the definition of the DC population based on CD11c expression, the time during infection at which the cells are assayed, and the dose of infected erythrocytes used to begin the blood-stage infection in the murine malaria model.…”

“…In playing such a central role in immunity, it is not surprising that the function of DCs is targeted by the parasite. Indeed, several studies in both humans (5,6) and mice (7)(8)(9)(10)(11)(12)(13)21) have documented changes in DC function in response to Plasmodium. In contrast, other reports have found fully functional DCs when exposed to parasites (14 -20).…”

“…However, malaria researchers have largely treated splenic DCs as a single, homogeneous population. Only recently, the possibilities of DC subsets playing different roles during the course of a murine Plasmodium infection have been explored (13,14,16,18), yet these reports have only considered conventional DCs which are identified by their high expression of the integrin ␣-chain CD11c. To attempt to reconcile the different DC phenotypes as seen by different research groups, we chose the context of a nonlethal murine Plasmodium infection that we had previously characterized in detail (8 -10) and decided to turn our attention to CD11c low -expressing DCs, a largely neglected subset of DCs.…”

Suppression of LethalPlasmodium yoeliiMalaria following Protective Immunization Requires Antibody-, IL-4-, and IFN-γ-Dependent Responses Induced by Vaccination and/or Challenge Infection

“…It is possible that such production of IFN-␥ helped to sustain protective Ab levels and/or was necessary for responses specifically required for MSP-specific Abs to be effective. Alternatively, the critical role for this early IFN-␥ production may be to enhance Ag processing and presentation by APCs and promote the initiation of protective immune responses to additional parasite Ags (33,65). A second wave of IFN-␥ production in rPyMSP-8 immunized mice was noted late during infection as parasitemia began to resolve.…”

Dendritic Cells in Plasmodium Infection

“…In simple terms, early on in infection when parasite density is relatively low, IL-12-mediated mechanisms induce IFN-γ-producing CD4 + T cells. This DC phenotype may be maintained over the entire course of infection with nonlethal strains of Plasmodium [45], although it is unclear how lethal and nonlethal strains differ with respect to the immune response they generate, and the influence of dose. Later, when parasite densities are peaking, DCs may become refractory to TLR and other signaling events, possibly due to overstimulation or due to TNF-α [46,47], thus abrogating IL-12 and TNF-α secretion, and as capacity to produce IL-10 increases.…”