The role of natural killer cells and antibodies in protection from malaria

Objectives

This proposal aims to understand how γ neg natural killer (NK) cells increase function and abundance in the context of malaria infection and to define NK cell antibody-dependent cellular cytotoxicity (ADCC) protective mechanisms against the placental malaria target Var2CSA, a protein on the surface of the infected RBC that adheres to the placenta and can cause miscarriages.

This objective will be achieved through:

• the use of CRISPR/Cas9 to ablate effector and adhesion molecules to understand how NK cells inhibit the growth of Plasmodium.
• to test the underlying mechanism of malaria exposure that drives the increase in γ neg NK cells and test if γ neg NK cells expand with ADCC and malarial cytokine signals.
• to test if antibodies that are good at generating NK cell ADCC responses increase with Var2CSA exposure and correlate with protective pregnancy outcomes in human and monkey samples.
• to test previously identified and novel monoclonal antibodies for NK cell ADCC function and dissect the features that generate a strong NK ADCC response.

These aims in total will create a body of work that will contribute to the development of better vaccines and therapeutics for malaria. This would change vaccine targets to be proteins on the surface of infected RBCs instead of invasion proteins, predictive efficacy readouts would include NK cell ADCC assays, and antibodies developed here may be future immune therapies.