Genetically Attenuated Plasmodium berghei Liver Stages Induce Sterile Protracted Protection That Is Mediated by Major Histocompatibility Complex Class I-Dependent Interferon-γ-Producing CD8+ T Cells

• Published in: The Journal of infectious diseases Vol. 196; no. 4; pp. 599 - 607
• Main Authors: Jobe, Ousman, Lumsden, Joanne, Mueller, Ann-Kristin, Williams, Jackie, Silva-Rivera, Hilda, Kappe, Stefan H. I., Schwenk, Robert J., Matuschewski, Kai, Krzych, Urszula
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 15.08.2007; University of Chicago Press
• Subjects: Animals; beta 2-Microglobulin - genetics; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Drug Evaluation, Preclinical; Female; Gene Deletion; Hepatocytes; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Human protozoal diseases; Immunity; Immunization; Immunization Schedule; Immunologic Memory; Infectious diseases; Interferon-gamma - biosynthesis; Liver; Liver - immunology; Malaria; Malaria - immunology; Malaria - prevention & control; Malaria Vaccines - administration & dosage; Malaria Vaccines - genetics; Medical genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Parasites; Parasitic diseases; Plasmodium berghei - genetics; Plasmodium berghei - growth & development; Protozoal diseases; Sporozoites; Sporozoites - immunology; T lymphocytes; Transcriptional regulatory elements; Vaccination; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - genetics; Immunoprotection; Protozoa; Apicomplexa; Protozoal disease; Malaria; Digestive system; Liver; Major histocompatibility system; Cytokine; Cellular immunity; Parasitosis; Infection; Plasmodium berghei; T-Lymphocyte; Class I histocompatibility antigen; Gamma interferon
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/519743

At present, radiation-attenuated plasmodia sporozoites (γ-spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, γ-spz are not without risks. For example, the heterogeneity of the γ-spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8+ T cells to protection. Pbuis3(-)/4(-) spz induced sterile andprotractedprotection in C57BL/6 mice. Protection was linked to CD8+ T cells, given that mice deficient in β2 m were not protected. Pbuis3(-)/4(-) spz-immune CD8+ T cells consisted of effector/memory phenotypes and produced interferon-γ. On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.