A Sporozoite Asparagine-Rich Protein Controls Initiation of Plasmodium Liver Stage Development

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Abstract
Plasmodium sporozoites invade host hepatocytes and develop as liver stages (LS) before the onset of erythrocytic infection and malaria symptoms. LS are clinically silent, and constitute ideal targets for causal prophylactic drugs and vaccines. The molecular and cellular mechanisms underlying LS development remain poorly characterized. Here we describe a conserved Plasmodium asparagine-rich protein that is specifically expressed in sporozoites and liver stages. Gene disruption in Plasmodium berghei results in complete loss of sporozoite infectivity to rodents, due to early developmental arrest after invasion of hepatocytes. Mutant sporozoites productively invade host cells by forming a parasitophorous vacuole (PV), but subsequent remodelling of the membrane of the PV (PVM) is impaired as a consequence of dramatic down-regulation of genes encoding PVM-resident proteins. These early arrested mutants confer only limited protective immunity in immunized animals. Our results demonstrate the role of an asparagine-rich protein as a key regulator of Plasmodium sporozoite gene expression and LS development, and suggest a requirement of partial LS maturation to induce optimal protective immune responses against malaria pre-erythrocytic stages. These findings have important implications for the development of genetically attenuated parasites as a vaccine approach. Plasmodium parasites, the causative agents of malaria, have a complex life cycle that alternates between a mosquito vector and a vertebrate host. Infected mosquitoes transmit Plasmodium forms called sporozoites, which rapidly migrate to the host liver, invade hepatocytes, and differentiate into replicative liver stages (LS). After intensive multiplication, LS release merozoites that invade erythrocytes and cause malaria symptoms. Plasmodium LS are clinically silent, and represent ideal targets for prophylactic antimalarial drug and vaccine interventions. However, the molecular mechanisms underlying LS development remain poorly characterized. We describe here a Plasmodium protein, termed SLARP, which is specifically expressed in sporozoites and LS. In the absence of SLARP, sporozoites invade host cells normally but are then completely arrested at a very early stage of LS development. Our results indicate that SLARP functions as a specific regulator of the expression of genes involved in LS replication. Interestingly, early arrested SLARP-deficient parasites confer only limited protection in immunized mice, suggesting a requirement of parasite maturation to induce optimal protective immune responses against LS. Our study provides new insights into gene expression regulation during the complex life cycle of the malaria parasite and has important implications for the design of vaccines targeting Plasmodium liver stages.