Abstract

Protection against P. berghei malaria can successfully be induced in mice by immunization with both radiation attenuated sporozoites (RAS) arresting early during liver stage development, or sporozoites combined with chloroquine chemoprophylaxis (CPS), resulting in complete intra-hepatic parasite development before killing of blood-stages by chloroquine takes place. We assessed the longevity of protective cellular immune responses by RAS and CPS P. berghei immunization of C57BL/6j mice. Strong effector and memory (TEM) CD8+ T cell responses were induced predominantly in the liver of both RAS and CPS immunized mice while CD4+ T cells with memory phenotype remained at base line levels. Compared to unprotected naïve mice, we found high sporozoite-specific IFNγ ex vivo responses that associated with induced levels of in vivo CD8+ TEM cells in the liver but not spleen. Long term evaluation over a period of 9 months showed a decline of malaria-specific IFNγ responses in RAS and CPS mice that significantly correlated with loss of protection (r2 = 0.60, p<0.0001). The reducing IFNγ response by hepatic memory CD8+ T cells could be boosted by re-exposure to wild-type sporozoites. Our data show that sustainable protection against malaria associates with distinct intra-hepatic immune responses characterized by strong IFNγ producing CD8+ memory T cells.

Highlights

  • Malaria is transmitted to the host through bites of Plasmodium infected mosquitoes that inject sporozoites into the skin

  • CD4+CD44hi or CD8+CD44hi T cell responses in peripheral blood mononuclear cells (PBMC), hepatic mononuclear cell (HMC) and splenocytes were similar for both tested regimens (Fig. 2a)

  • The present study highlights the essential role of IFNc response by liver memory CD8+ T cell for the longevity of protection against malaria

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Summary

Introduction

Malaria is transmitted to the host through bites of Plasmodium infected mosquitoes that inject sporozoites into the skin. These sporozoites travel to the liver for further development and released as blood-stage parasites that are responsible for clinical malaria [1]. A number of whole-parasite models including sporozoites or blood-stage parasites are currently in use to study mechanisms of protective immunity [2,3,4]. In the CPS approach, the anti-malarial drug chloroquine (CQ) rapidly clears parasites from the bloodstream without affecting the liver stages [6] while allowing the host to mount a fully protective immune response

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