Abstract
Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.
Highlights
Malaria is transmitted through the bite of an infected mosquito, which introduces Plasmodium sporozoites into the mammalian host
To determine whether the blood stage of the parasite is the cause for the observed lack of CD8ϩ T cell response in normal infections, we immunized groups of mice with P. yoelii–irradiated sporozoites 10 d before inducing a blood stage infection by the transfer of P. yoelii–infected erythrocytes
We observed that blood stage infection inhibited the previously established CD8ϩ T cell response induced by irradiated sporozoites (Fig. 1 b), indicating that blood stage malaria suppresses previously established CD8ϩ T cell responses against a liver stage antigen
Summary
Malaria is transmitted through the bite of an infected mosquito, which introduces Plasmodium sporozoites into the mammalian host. Sporozoites rapidly reach the liver of the host where they develop and replicate into merozoites, the parasitic stage that infects erythrocytes and causes the pathology of the disease It is unclear why natural infections do not induce protection against the initial liver stage of Plasmodium and generate only low cytotoxic CD8ϩ T cell responses [1,2,3]. In endemic areas, this lack of protection against liver stage infection results in constant malaria reinfections throughout life [2]. Protection is mediated by high CD8ϩ T cell responses specific against infected hepatocytes [6]
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