Targeting APC-Host Microbe interactions 1Antigen presentation for liver-stage immunity to Plasmodium Infection

Abstract

Malaria is a highly prevalent parasitic disease, accounting for approximately 216 million infections and 445,000 deaths per annum. Disease is caused by Plasmodium spp. and is transmitted via female Anopheles mosquitoes. Following a bite from an infected mosquito, immature parasites (sporozoites) are released into the skin and migrate via the blood to the liver where they asymptomatically infect hepatocytes. Within a few days, sporozoites replicate and mature within hepatocytes before entering the blood as merozoites. This merozoites infect red blood cells and cause all disease symptoms. More than 30 years ago, it was shown that malaria could be prevented by vaccination with radiation attenuated sporozoites (RAS). However, development of an effective vaccine has been problematic. Protective immunity induced by RAS vaccination is in part mediated by antibody, which blocks sporozoite migration to the liver, and in part by CD8 T cells, which kill infected hepatocytes. For the latter component, tissue-resident memory CD8 T cells in the liver are the primary mediators of protection. We have explored the requirements for generation of T cell immunity to sporozoites, and the factors that control liver CD8 Trm cell development, seeding and function. This has led to the identification of target antigens and to the development of vaccination approaches that favour liver Trm cell formation and are protective against sporozoite challenge. Aspects of these studies will be discussed.