Late killing ofPlasmodium bergheiin the liver by an anti-circumsporozoite protein monoclonal antibody

Abstract

AbstractThe transmission ofPlasmodiumparasites into the vertebrate host skin begins with the inoculation of a few sporozoites during the bite of an infected mosquito. This motile stage invades cutaneous blood vessels to reach the liver and infect hepatocytes. The first approved malaria vaccine RTS, S/AS01 elicits high titers of antibodies against the circumsporozoite protein (CSP), the main protein on the surface of sporozoites. Protection mainly unfolds during parasite migration through the host, but rare and potent protective antibodies can additionally neutralize sporozoite in the blood and liver. Here, using microscopy and bioluminescence imaging in a rodent malaria model, we show the dynamics of parasite elimination in the liver by the 3D11 anti-CSP monoclonal antibody (mAb) targeting the repetitive region of thePlasmodium bergheiCSP. Our data confirmed that in passively immunized mice protection against an intravenous sporozoite challenge requires much higher concentrations of antibody than a cutaneous challenge adjusted to elicit the same level of infection. Sporozoite arrest in the liver was not affected by the protective antibody. A two-fold decrease in the crossing of the hepatic sinusoidal barrier was observed after three hours post sporozoite inoculation, associated with the loss of parasite motility. Intriguingly, the elimination of most parasites in the liver occurred after 5 hours post-inoculation, indicating a late action of this protective antibody.In vitro, 3D11 strongly inhibited the invasion of HepG2 cells by sporozoites in positive correlation with its cytotoxic activity. Additionally, this protective mAb impaired the intracellular development of liver stages, confirming the late cytotoxic effect of this antibody. Altogether, 3D11-mediated protection in the liver is mainly associated with its cytotoxic activity, which leads to the inhibition of sporozoite motility, sinusoidal extravasation, cell invasion, and to the killing inside the liver parenchyma.