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

Abstract

Immunization with Plasmodium sporozoites that have been attenuated by ␥-irradiation or specific genetic modification can induce protective immunity against subsequent malaria infection. The mechanism of protection is only known for radiation-attenuated sporozoites, involving cell-mediated and humoral immune responses invoked by infected hepatocytes cells that contain longlived, partially developed parasites. Here we analyzed sporozoites of Plasmodium berghei that are deficient in P36p (p36p ؊ ), a member of the P48͞45 family of surface proteins. P36p plays no role in the ability of sporozoites to infect and traverse hepatocytes, but p36p ؊ sporozoites abort during development within the hepatocyte. Immunization with p36p ؊ sporozoites results in a protective immunity against subsequent challenge with infectious wild-type sporozoites, another example of a specifically genetically attenuated sporozoite (GAS) conferring protective immunity. Comparison of biological characteristics of p36p ؊ sporozoites with radiation-attenuated sporozoites demonstrates that liver cells infected with p36p ؊ sporozoites disappear rapidly as a result of apoptosis of host cells that may potentiate the immune response. Such knowledge of the biological characteristics of GAS and their evoked immune responses are essential for further investigation of the utility of an optimized GAS-based malaria vaccine.apoptosis ͉ attenuated vaccines ͉ host-pathogen interaction ͉ Plasmodium

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

“…P36p, a member of a small family of Plasmodium proteins that have 6 conserved cysteine residues has recently been shown in the rodent malaria parasite Plasmodium berghei to be important for early stages of hepatocyte infection, although some controversy exists as to whether it is required for the invasion process itself or early development in the hepatocyte [75,76]. The Py235 rhoptry proteins, first described in Plasmodium yoelii but with clear homologues in other rodent and human malaria species, are encoded by a multigene family with differential expression during the life cycle (reviewed in [77]).…”

Genetically Attenuated Parasite Vaccines Induce Contact-Dependent CD8+ T Cell Killing of Plasmodium yoelii Liver Stage-Infected Hepatocytes

“…I rradiated and genetically attenuated Plasmodium sporozoites (spz) 3 are among the most promising pre-erythrocytic malaria vaccine candidates, as both provide complete and longlasting protection in rodent models of malaria (1)(2)(3)(4)(5)(6)(7). Irradiated spz have been found to induce complete protection in humans (4), and a human trial for a genetically attenunated parasite vaccine is underway as well.…”

Protective immunity against malaria liver stage after vaccination with live parasites

“…One potential major limitation of this approach is the possible occurrence of breakthrough infections. This has been observed for the IUS-4 -and the p36-sporozoites van Dijk et al, 2005). To circumvent this problem, deficient parasites for two antigens UIS3 and UIS4 (Jobe et al, 2007) or P52 and P36 have been created and displayed no such events.…”

“…In a series of elegant studies, a number of genes expressed by the sporozoite in the developing liver stages have been identified). Inactivation of the genes coding for the proteins IUS3, IUS4, or P36p, P52 and P36 (Mueller et al, 2005a(Mueller et al, , 2005bVan Dijk et al, 2005;Labaied et al, 2007;Jobe et al, 2007) in P. berghei or P. yoelii resulted in parasites that could not complete liver stage development. These genetically altered sporozoites were recognised to reproduce the phenotype of irradiated sporozoites.…”