PROJECT SUMMARY_____________________________________________________________________
Parasitic diseases remain a problem worldwide largely due to the lack of vaccines to effectively interrupt
transmission or infection, as parasites often develop resistance to drugs. A combination of different factors
principally drives the lack of vaccines against parasitic diseases, including a limited understanding of the nature
of the humoral immune response and difficulties in proper expression of the candidate immunogen. Our current
work suggests that the GPI anchor has a vital role in humoral immune response to GPI-anchored proteins (GPI-
APs) and most vaccine efforts have utilized GPI-APs - which constitute the bulk of surface proteins in parasites,
as immunogens. However, in these vaccine formulations, the GPI-APs are without the GPI anchor to enable
soluble expression of such proteins. In this grant submission, we have shown that de-lipidation of the GPI anchor
significantly reduces antibody reactivity to GPI-APs of Toxoplasma gondii, a widespread Apicomplexa parasite
of animals. We hypothesize a role of the GPI anchor in humoral immune response and propose using mRNA
technology as an efficient method for accurate delivery of GPI-APs to the immune system to understand its role
following vaccination. We also propose the use of mRNA vaccines for the efficient delivery of highly conserved
antigens of the parasite's invasion machinery, a handful of which we propose as excellent targets to halt invasion
of apicomplexans. Thus, we will employ tools in immunology, molecular parasitology, vaccinology, and
biochemistry to dissect the aims of the study. In Aim 1, the role of the GPI anchor in humoral immunity to T.
gondii will be deciphered by comparing vaccine efficacies of parasite GPI-APs with and without their GPI
anchorage following immunization. In Aim 2, the invasion machinery of T. gondii will be targeted by vaccine-
elicited antibodies against conserved apical proteins of the plasma membrane that confer fitness to the parasite.
With the overall goal of the project being to block infection of T. gondii and apicomplexans in general, this R21
proposal will provide new insights in vaccine development against parasitic diseases.
