Plasmodium liver stage developmental arrest by depletion of a protein at the parasite–host interface

Abstract

Plasmodium parasites of mammals, including the species that cause malaria in humans, infect the liver first and develop there into clinically silent liver stages. Liver stages grow and ultimately produce thousands of first-generation merozoites, which initiate the erythrocytic cycles causing malaria pathology. Here, we present a Plasmodium protein with a critical function for complete liver stage development. UIS4 (up-regulated in infective sporozoites gene 4) is expressed exclusively in infective sporozoites and developing liver stages, where it localizes to the parasitophorous vacuole membrane. Targeted gene disruption of UIS4 in the rodent model malaria parasite Plasmodium berghei generated knockout parasites that progress through the malaria life cycle until after hepatocyte invasion but are severely impaired in further liver stage development. Immunization with UIS4 knockout sporozoites completely protects mice against subsequent infectious WT sporozoite challenge. Genetically attenuated liver stages may thus induce immune responses, which inhibit subsequent infection of the liver with WT parasites. attenuated parasite ͉ malaria ͉ parasitophorous vacuole ͉ stage-specific gene expression

Evidence from NMR interaction studies challenges the hypothesis of direct lipid transfer from L‐FABP to malaria sporozoite protein UIS3

“…8,9 A central role of UIS3 in fatty acid uptake has been recently proposed. 10 Indeed, a yeast two-hybrid screen based on UIS3 of the rodent malaria parasite P. yoelii (Py-UIS3) identified mouse liver fatty acid binding protein (mL-FABP) as an interacting host protein.…”

Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design

“…Recently, preerythrocytic stages of the rodent malaria parasites Plasmodium berghei and Plasmodium yoelii were attenuated by deletion of preerythrocytic-stage-expressed genes named Up-regulated in Infectious Sporozoites (UISs). UIS3 and UIS4 (7)(8)(9) are proteins of the liver-stage parasitophorous vacuole membrane, the principal host-parasite interface during liver infection (7,10). Deletion of UIS3 and UIS4 led to complete arrest of early liver-stage development after hepatocyte infection (7)(8)(9).…”

“…UIS3 and UIS4 (7)(8)(9) are proteins of the liver-stage parasitophorous vacuole membrane, the principal host-parasite interface during liver infection (7,10). Deletion of UIS3 and UIS4 led to complete arrest of early liver-stage development after hepatocyte infection (7)(8)(9). Deletion of another UIS gene, P52, encoding a putative GPI-anchored protein (11,12), and P36, a gene encoding a putative secreted protein (12), also resulted in developmental arrest at the early stage of hepatocyte infection.…”

Genetically attenuated, P36p-deficient malarial sporozoites induce protective immunity and apoptosis of infected liver cells

“…Parasites that are underirradiated remain infectious, and those that are overirradiated do not induce protective immunity. Recently, it has been shown that genetically attenuated sporozoites (GAS) that lack sporozoitespecific conserved genes (uis3 and uis4) that are apparently important for sporozoite development in the hepatocyte can induce significant or complete protective immunity in the P. berghei rodent model of malaria when different immunization protocols are used (16,17). The use of GAS for vaccination might remove the uncertainty associated with RAS once a more thorough understanding of the mechanisms of immunity invoked by GAS and their developmental defect(s) are available.…”