B1 Immune correlates of protective pre-erythrocytic immunity against Plasmodium berghei infections (Matuschewski)
|Research Group:||Parasitology Unit|
|Address:||Humboldt-Universität zu Berlin, Department of Biology, Molecular Parasitology, Philippstr. 13, House 14, 10115 Berlin|
|Supervisor:||Prof. Dr. Kai Matuschewski, Dr. Katja Müller|
|Doctoral Researcher:||Calvin Hon, Tinghuan Song|
State of the art:
Recognition of Plasmodium pre-eyrthrocytic stages and the generation of protective immune
responses during the clinically silent, obligate first replication phase in the liver remain largely
unexplored. A better immunological understanding of the molecular mechanisms that lead to
naturally acquired or vaccine-induced immunity is critical for understanding transmission
dynamics in the field and novel evidence-based intervention tools, respectively. Genetically
arrested parasites (GAPs) combine the potency of whole parasite vaccines with tailor-made
reverse genetic engineering to achieve lasting protection against reinfection, which is not
observed during continuous exposure in malaria-endemic areas. Critical knowledge gaps
include the roles of protein export and cytotoxic T cells in elimination of infected hepatocytes,
the potential of multiple gene knockouts and adjuvanted sporozoites to improve vaccine
efficacy, and the immune correlates of protection against pre-eyrthrocytic Plasmodium stages.
Previous own work:
Generation of transgenic parasites expressing an extra copy of a central protein export
regulator under the control of a strong pre-erythrocytic promoter revealed severe growth
defects in liver stage development in vitro and in vivo. Animals immunized with transgenic
parasites displayed weak protection against sporozoite challenge infections. These results
suggest that protein export is tightly controlled to maintain sporozoite infectivity and minimize
exposure of parasite-derived peptides on the surface of infected hepatocytes. Generation of a
live attenuated parasite line that is non-protective can now be used to differentiate immune
signatures of protection and sporozoite exposure. Comparative analysis of protective efficacy
of a double knockout GAP line revealed inferior protection, correlates with rapid declines in
antigen-specific CD8+ IFNγ+ T cell responses.
Hypotheses and work plan:
1) A carry-along adjuvant (Salmonella enterica flagellin) in transgenic P. berghei sporozoites
might potentially improve malarial vaccine efficacy.
2) Comparison of CD8+ IFNγ+ T cell immune profiles of murine models immunized with
protective and non-protective vaccine lines can uncover signatures of immune protection
against correlates of parasite exposure.
3) Ablation of the T cell epitopes from parasite antigens will directly address the significance
of CD 8+ T cell epitopes for protective immunity against P. berghei.
4) Study and transfer of the sibling species P. cyclopsi from the insectivorous bat Hipposideros
cyclops to the lab will allow to determine whether GAPs protect against heterologous challenge
infections, what genetic signatures determine host specificity, and whether P. cyclopsi-infected
bats display signature of anti-sporozoite immunity.
Together, these studies will provide critical insights into vaccine-induced and naturally acquired