Elimination of P. berghei liver stages is independent of Fas (CD95/Apo‐I) or perforin‐mediated cytotoxicity

Abstract

Immunization of mammals with irradiated malaria sporozoites protects from a subsequent contact with the parasite. Protective immunity is directed against the pre‐erythrocytic stages of the parasite, sporozoites and liver stages. Specific antibodies neutralize part of the infectious sporozoites injected by the mosquito vector, while liver stages are the target of a cellular immune response which is mediated by T cells. In this study, we evaluated the T‐cell dependent protection induced by the injection of P. berghei irradiated sporozoites and the contribution of perforin and of the receptor/ligand system CD95/CD95L, two T cell‐dependent mechanisms known to mediate elimination of target cells. Wild type, perforin deficient, CD95 mutant, CD95L mutant and perforin deficient/CD95L mutant mice were immunized with P. berghei irradiated sporozoites and submitted to a challenge with infectious sporozoites. All mice immunized with P. berghei irradiated sporozoites were protected against a sporozoite challenge, including perforin deficient/CD95L mutant animals. These results indicate that T cells do not kill malaria‐infected hepatocytes via one of the known pathways, but rather that activated parasite‐specific T cells produce cytokines which activate in cascade other mechanisms responsible for the intracellular elimination of the parasite.

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

“…This is in conformity with studies which have shown that infected cells are protected from apoptosis (42,43). In addition, the finding that Fas-and perforin-deficient mice could still be protected from P. berghei (44) and P. yoelii (45) infection suggests that other mechanisms are implicated in the destruction of hepatic forms. It is interesting to note that even though infected cells did not undergo apoptosis, neighboring noninfected cells (probably traversed by sporozoites) readily underwent apoptosis upon addition of specific CTLs (Fig.…”

“…However, further studies are needed to determine whether this mechanism is operative in vivo. Nevertheless, the fact that protection could still be observed in Fas-and perforin-deficient mice (44) suggests that infected cells do not undergo apoptosis in vivo.…”

CD8+T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection

“…An earlier study suggested that perforin-or Fas-mediated killing is not the main pathway of parasite elimination during the hepatic stage of the infection (45). Additionally, a recent study using CSP-specific transgenic T cells suggested that IFN-␥ is not essential for the protection of mice against infection with P. yoelii sporozoites (46).…”

Genetic Vaccination against Malaria Infection by Intradermal and Epidermal Injections of a Plasmid Containing the Gene Encoding thePlasmodium bergheiCircumsporozoite Protein

“…Protection induced by immunization with X-irradiated P. berghei sporozoites depends upon the response of antibody, CD8ϩ T cells, and IFN-␥ (27) as well as MHC class I (36) but not CD8ϩ CTLs (23). Protection induced by immunization with recombinant adenovirus-CSP against P. yoelii sporozoite infection depends upon CD8ϩ T-cells but not upon IFN-␥ (24).…”