Abstract
Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8+ T cell memory responses to LS infection. It is reported that CD8α+ dendritic cells (DCs) are involved in the induction of LS-specific CD8+ T cells following RAS or genetically attenuated parasite (GAP) vaccination. In this study, we demonstrate that CD8α+ DCs respond differently to infectious sporozoite or RAS inoculation. The higher accumulation and activation of CD8α+ DCs was seen in the liver in response to infectious sporozoite 72 h postinoculation and found to be associated with higher expression of chemokines (CCL-20 and CCL-21) and type I interferon response via toll-like receptor signaling in liver. Moreover, the infectious sporozoites were found to induce qualitative changes in terms of the increased MHCII expression as well as costimulatory molecules including CD40 on the CD8α+ DCs compared to RAS inoculation. We have also found that infectious sporozoite challenge increased CD40L-expressing CD4+ T cells, which could help CD8+ T cells in the liver through “licensing” of the antigen-presenting cells. Our results suggest that infectious sporozoite challenge to prior RAS immunized mice modulates the CD8α+ DCs, which might be shaping the fate of memory CD8+ T cells against Plasmodium LS infection.
Highlights
Malaria still remains a serious challenge to human health as millions of lives are at the risk of infection, the children residing in South-East Asia and Sub-Saharan Africa [1]
Since radiation-attenuated sporozoites (RAS) immunized mice were protected for 6 months, we sought to determine the reactivation potential of CD8+ T cells after 6 months in order to find out the differences between RAS and Inf
The data were analyzed with non-parametric Mann–Whitney U-test. p < 0.05 is considered as a significant
Summary
Malaria still remains a serious challenge to human health as millions of lives are at the risk of infection, the children residing in South-East Asia and Sub-Saharan Africa [1]. We have shown that the protection could be extended from 6 to 18 months in mice by the intermittent challenge with infectious sporozoites (Inf. Spz) [11] (manuscript in preparation). We have shown that the loss of CD8+ T cells in the liver of RAS immune mice is rescued following the Inf. Spz challenge. It has been shown that host (rodent as well as human) immunized with Inf. Spz under the cover of chloroquine are protected up to 28 months [20, 21]. The above findings are indicative of the fact that infectious status of sporozoites may be playing a key role in modulating CD8+ T cell response that ensue longer-lived protection against Plasmodia LS infection
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