Plasmodium infection cure cycles induce modulation of conventional dendritic cells

Abstract

Malaria is one of the most widespread human infectious diseases worldwide and a cause of mortality. It is difficult to induce immunological memory against the malarial parasite Plasmodium. The immunity to clinical malaria disease is acquired with multiple infection and treatment cycles, along with substantial reduction in parasite burden. However, the mechanism of the acquired immunity remains largely unclear. Conventional DCs (cDCs) play a pivotal role in orchestration of immune responses. The purpose of this study is to analyze the characterization of cDCs after the infection and cure treatment cycles. Mice were infected with the lethal rodent malarial parasite Plasmodium berghei ANKA, which was followed by cure treatment with the antimalarial drug pyrimethamine. This was then followed by a challenge with live parasites. The mice that went through infection cure cycles showed significant immune response, demonstrating robust immunological memory against malaria parasites. We investigated the cytokine production capacity of splenic cDCs in both naive and infection cure mice by stimulating purified splenic cDCs with LPS (TLR4 agonist) or CpG (TLR9 agonist). The capacity of cytokine production was found to be significantly decreased in infection cure mice. The suppression of cytokine production was sustained for a long term (6 months). Moreover, the surface expression of MHC Class II molecules was significantly lower in infection cure mice than in naive mice. These results suggest that Plasmodium infection and cure treatment resulted in strong immunological memory and modulation of full functionality of cDCs.

Keywords: cytokine production; dendritic cells; infection cure treatment; malaria; trained immunity.