Research

BACKGROUND | Malaria is caused by a parasite of the Plasmodium species that is transmitted from human to human by a mosquito. During the stage of the parasite’s life cycle that causes symptomatic disease in the human host, the parasite replicates inside red blood cells. Infected individuals develop an immune response against this stage of the parasite. In endemic regions, people often experience many episodes of malaria in their life, which boosts their immune response against the parasite to a level that protects against symptomatic disease. However, these protective immune responses take years to develop, leaving children highly susceptible to severe disease and death. A better understanding of the development of immunological protection would be an important contribution towards the design of a malaria vaccine.

PROJECTS | The Bunnik lab aims to increase our knowledge about protective immune responses by learning from nature, i.e. by studying immune responses elicited as a result of natural infection. In collaboration with Dr. Bryan Greenhouse at the University of California San Francisco we use samples from the East-Africa International Center of Excellence in Malaria Research in Tororo, Uganda. In addition to host immune responses, we are also interested in the mechanisms that regulate gene expression in the parasite. We currently work on five main projects.

One | The development of antibody responses against merozoite antigens. Merozoites express many different proteins that play a role in the invasion of erythrocytes. Many of these proteins are potential candidates for vaccine development. However, extensive genetic diversity in these antigens between different parasite strains impairs the elicitation of strain-transcending antibody responses. Studies of naturally acquired immunity suggest that malaria-protected individuals harbor strain-transcending antibodies that target conserved epitopes. We aim to identify and characterize these conserved epitopes and study how antibody responses against these polymorphic merozoite antigens develop over the course of life-long Plasmodium falciparum exposure.

Two | Broadly reactive antibodies against the PfEMP1 CIDRα1 domain associated with severe malaria. Malaria pathology is driven by the accumulation of parasite-infected erythrocytes in capillaries. This process is mediated by the binding of the variant surface antigen PfEMP1 to host receptors on the vascular endothelium. A subset of PfEMP1 variants that contains a CIDRα1 domain and can bind to host endothelial protein C receptor (EPCR) is responsible for pathogenesis of severe malaria. Naturally exposed individuals rapidly develop protection against severe malaria and harbor antibodies against CIDRα1 domains. In collaboration with Dr. Thomas Lavstsen at the University of Copenhagen, we are isolating and characterizing monoclonal antibodies that are able to inhibit the interaction between CIDRα1 and EPCR. We aim to understand how common antibodies with reactivity against a wide range of different CIDRα1 domains are and how these broadly reactive antibodies interact with diverse CIDRα1 domains to inhibit EPCR binding.

Three | The phenotype and development of memory B cells. Recent studies have provided insight into various subsets of memory B cells that can be distinguished by surface marker expression and transcriptome. The function of these different B cell subsets and their role in immunity against malaria is incompletely understood. Using a combination of high-parameter flow cytometry and single-cell sequencing, we aim to better understand how B cells respond to different antigens and which B cell responses underlie long-lived immunological memory.

Four | The origin and fate of atypical memory B cells. Chronic and frequently recurring infectious diseases, such as malaria, are commonly associated with expanded populations of atypical memory B cells (atMBCs). While the phenotype and conditions leading to the generation of atMBCs in malaria-experienced individuals have extensively been studied, the origin and fate of these cells remain largely elusive. Using B cell receptor (BCR) sequencing to track clonally related cells, we aim to better understand the development and differentiation pathways of atMBCs in Plasmodium-exposed individuals.

Five | Epigenetic, transcriptional, and post-transcriptional regulation of gene expression in Plasmodium falciparum. During the process of egress and re-invasion, transcriptionally active schizonts transition to merozoites with little to no transcriptional activity, followed by restarting gene expression upon re-invasion and establishment of ring stages. We aim to map changes in the epigenetic landscape during the schizont-to-ring transition and explore additional layers of regulation of gene expression at the transcriptional and post-transcriptional levels.

Bunnik lab

San Antonio, Texas, 2021