Dendritic Cell Responses and Function in Malaria

Abstract

Malaria remains a serious threat to global health. Sustained malaria control and, eventually, eradication will only be achieved with a broadly effective malaria vaccine. Yet a fundamental lack of knowledge about how antimalarial immunity is acquired has hindered vaccine development efforts to date. Understanding how malaria-causing parasites modulate the host immune system, specifically dendritic cells (DCs), key initiators of adaptive and vaccine antigen-based immune responses, is vital for effective vaccine design. This review comprehensively summarizes how exposure to Plasmodium spp. impacts human DC function in vivo and in vitro . We have highlighted the heterogeneity of the data observed in these studies, compared and critiqued the models used to generate our current understanding of DC function in malaria, and examined the mechanisms by which Plasmodium spp. mediate these effects. This review highlights potential research directions which could lead to improved efficacy of existing vaccines, and outlines novel targets for next-generation vaccine strategies to target malaria.

Dendritic cell responses to Plasmodium falciparum in a malaria-endemic setting

“…The biology of primary human DCs is understudied due in part to their low frequencies in peripheral blood and the technical di culties of relevant experimental assays. Our understanding of primary human DC responses to P. falciparum in particular remains very limited (reviewed in [44]). In light of evidence that the leading malaria vaccine candidate RTS,S confers only partial, short-lived protection in African children [4], it is of great importance to gain a better understanding of DC responses, particularly in malariaendemic settings.…”

Immune effector mechanisms in malaria: An update focusing on human immunity

“…IFNα‐mediated pDC crosstalk with cDC1 (CD141+, BDCA3+) enhance phagocytosis of parasitized‐RBCs or free merozoites, whereby cDC1 become MHC Class II restricted antigen‐presenting cells (APCs) that secrete cytokines to instruct naïve CD4+ T cell differentiation or cross‐present antigens via the alternate pathway for MHC I‐restricted induction of cytotoxic CD8+ T cells, which has been described for P. falciparum . Transcriptional profiling of human immune cells has also begun to reveal atypical interactions between DCs and parasitized‐RBCs . Newly named “ bona fide” DCs co‐cultured in vitro with parasitized‐RBCs expressed low levels of inflammatory Th1 cytokines (ie, IL1β, IL6, IL10 and TNF) and yet were still able to activate naïve CD4+ T cells to proliferate and secrete Th1 cytokines (ie, IFNγ and TNF).…”

“…However, investigating the critical role of human DCs during the course of malaria has been severely hindered by their extremely low frequency in peripheral blood (0.5%‐1.0%, ~25 000 DCs/1 mL whole blood). Human DCs have been classified into two major subtypes (distinct from monocytes), plasmacytoid DCs (pDCs) and conventional DCs (CD1) distinguished by expression of CD11c and CD123 (reviewed in ). Single‐cell RNA‐sequencing (scRNAseq) and unbiased computational methods are being used to further define DC subsets by blood dendritic cell antigens (BDCA), assign function and understand ontogeny in human blood .…”

“…116 Transcriptional profiling of human immune cells has also begun to reveal atypical interactions between DCs and parasitized-RBCs. 115,117 Newly named "bona fide" DCs co-cultured in vitro with parasitized-RBCs expressed low levels of inflammatory Th1 cytokines (ie, IL1β, IL6, IL10 and TNF) and yet were still able to activate naïve CD4+ T cells to proliferate and secrete Th1 cytokines (ie, IFNγ and TNF). This contradiction puts into question mechanisms of "DC suppression" during malaria (reviewed in 115,118 ).…”

“…115,117 Newly named "bona fide" DCs co-cultured in vitro with parasitized-RBCs expressed low levels of inflammatory Th1 cytokines (ie, IL1β, IL6, IL10 and TNF) and yet were still able to activate naïve CD4+ T cells to proliferate and secrete Th1 cytokines (ie, IFNγ and TNF). This contradiction puts into question mechanisms of "DC suppression" during malaria (reviewed in 115,118 ). Of note, P. falciparum-induced transcriptional profiles were compared to publically available transcriptomes of DCs stimulated by 13 microbial vaccines…”