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Abstract
The liver stages of malaria are clinically silent but have a central role in the Plasmodium
life cycle. Liver stages of the parasite containing thousands of merozoites grow inside
hepatocytes for several days without triggering an inflammatory response. We show
here that Plasmodium uses a PEXEL/VTS motif to introduce the circumsporozoite (CS)
protein into the hepatocyte cytoplasm and a nuclear localization signal (NLS) to enter
its nucleus. CS outcompetes NFkappaB nuclear import, thus downregulating the expression
of many genes controlled by NFkappaB, including those involved in inflammation. CS
also influences the expression of over one thousand host genes involved in diverse
metabolic processes to create a favorable niche for the parasite growth. The presence
of CS in the hepatocyte enhances parasite growth of the liver stages in vitro and
in vivo. These findings have far reaching implications for drug and vaccine development
against the liver stages of the malaria parasite.