Bunnik lab

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A mosquito taking a blood meal and erythrocytes infected with malaria-causing Plasmodium parasites.
BACKGROUND | Every minute, a young child dies of malaria. Almost all malaria patients live in Africa, and about 75% of the patients who die from malaria are children under the age of five. This devastating disease is caused by a parasite of the Plasmodium species that is transmitted from human to human by a mosquito. Symptomatic disease occurs when the Plasmodium parasites replicate inside erythrocytes. Infected individuals develop an immune response against these blood stage parasites. In endemic regions, people often experience many episodes of malaria, especially early in their life, which—over time—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.
In the Bunnik lab we study antibody and B cell responses in people who have had malaria to understand how these responses protect against the disease, with the overarching goal to facilitate the design of more effective malaria vaccines. In addition to host immune responses, we are also interested in the mechanisms that regulate gene expression in the parasite, with the goal to identify novel targets for anti-malarial drugs.
"We study how antibody and B cell responses protect against malaria in people with life-long parasite exposure, and, on the flip side, how such chronic immune activation affects the immune system."   —Dr. Evelien Bunnik
PROJECTS | In the Bunnik lab we aim 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 people living in the malaria-endemic region of Tororo in Uganda. We exclusively use human samples and in vitro culture systems to study host immune responses and parasite development, and do not rely on any non-human animal models. There are two important reasons for this: 1) We believe that all vertebrates are sentient and empathic beings [1,2,3,4,5,6,7,8,9], and do not feel comfortable using them for scientific experiments. 2) We believe that human immune responses and the effect of repetitive Plasmodium infections are difficult to model in a non-human animal. By working with human samples, our findings have high translational value.

We currently work on the following four projects, and have openings for both Ph.D. and master students.
PROJECT ONE | Isolating and characterizing antibodies that can inhibit parasite invasion

P. falciparum expresses a multitude of 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 hampers vaccine development. We aim to identify conserved epitopes on these polymorphic antigens and study how antibodies against these antigens inhibit parasite invasion. We do this by isolating monoclonal antibodies from memory B cells and determining where on the antigen these antibodies bind and to what extent they inhibit invasion. We collaborate with Dr. Greg Ippolito and Dr. Jason Lavinder at UT Austin who perform mass spectrometry analysis of antibodies against invasion proteins in the serum to compare memory B cell and serum antibody responses. We also work together with Dr. Marie Pancera at the Fred Hutchinson Cancer Center to solve structures of monoclonal antibodies in complex with their antigen.

This project is funded by NIH grant R01 AI153425 – Defining conserved epitopes on polymorphic malaria antigens.

Related publication from the Bunnik lab:
A molecular analysis of memory B cell and antibody responses against Plasmodium falciparum merozoite surface protein 1 in children and adults from Uganda | Jake Gonzales et al. | Frontiers in Immunology (2022)
Left: Expansion microscopy image of a mature parasite that has divided into individual merozoites. Total protein is shown in green and RAP-1, an invasion protein located in the rhoptry bulb, is shown in yellow. Middle: A collection of merozoites that has egressed from an erythrocyte. Right: Immunofluorescence image showing merozoites with Merozoite Surface Protein 1 in green and DNA in blue.
PROJECT TWO | Identifying broadly inhibitory antibodies against the PfEMP1 CIDRα1 domain that can protect against severe malaria

Malaria pathology is driven by the accumulation of parasite-infected erythrocytes in capillaries. This process is mediated by the binding of a parasite protein (PfEMP1) on the surface of the erythrocyte to receptors on the human vascular endothelium. A subset of PfEMP1 variants that contains a CIDRα1 domain are responsible for pathogenesis of severe malaria through binding to host endothelial protein C receptor. People living in malaria-endemic regions rapidly develop protection against severe malaria and harbor antibodies against CIDRα1 domains. In collaboration with Dr. Thomas Lavstsen at the University of Copenhagen in Denmark, we are isolating and characterizing monoclonal antibodies that are able to inhibit the interaction between CIDRα1 and endothelial protein C receptor. 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 binding to the human endothelium.

Related publication from the Bunnik lab:
Broadly inhibitory antibodies against severe malaria virulence proteins | Raphael Reyes et al. | sent out for peer-review by Nature | bioRxiv
PROJECT THREE | Understanding the role and significance of atypical B cells in the immune response to malaria and rheumatoid arthritis

Conditions of chronic and frequently recurring immune activation, as seen during Plasmodium infections and in autoimmune diseases, are commonly associated with expanded populations of atypical B cells. Whether these atypical B cells contribute to control of infections or negatively affect the host immune response remains incompletely understood. We recently showed that atypical B cells can be divided into three distinct cell populations, each with different properties and functions in the immune response. We are now studying what the protective potential and developmental drivers of subpopulations of atypical B cells are in the immune response to Plasmodium falciparum infections.
We are also interested in comparing atypical B cells between malaria-experienced individuals and rheumatoid arthritis patients, with the goal of finding similarities and differences that give us more information about the role(s) of atypical B cells in the immune response to infection and in autoimmunity. In this project, we collaborate with Dr. Agustin Escalante for the recruitment of RA patients, and Dr. Ferhat Ay for the analysis of omics data sets.

This project is funded by the Voelcker Fund Young Investigator Award – Characterizing atypical B cells as a therapeutic target in rheumatoid arthritis.

Related publication from the Bunnik lab:
Atypical B cells consist of subsets with distinct functional profiles | Raphael Reyes et al. | iScience (2023)
Single cell transcriptomics analysis identified three subsets of atypical B cells (left) that can be distinguished in flow cytometry by CD11c and CD86 expression (right).
PROJECT FOUR | How is gene expression regulated in Plasmodium falciparum?

Inside an erythrocyte, P. falciparum divides into 16 – 32 daughter cells over the course of approximately 48 hours. Once these daughter parasites—called merozoites—are mature, they will egress and invade a new erythrocyte to start the next cycle of replication. We are interested in understanding how gene expression during merozoite development and the transition of parasites from one host cell to the next is regulated. We use single-cell sequencing approaches to map gene co-expression networks in merozoites at high resolution and learn more about the regulatory mechanism(s) that control their development. Additionally, we aim to characterize the role of select transcription factors during this phase of the parasite’s life cycle. Our collaborators on this project are Dr. Kirsten Hanson from the University of Texas San Antonio and Dr. Ian Cheeseman from the Texas Biomedical Research Institute.

This project is funded by a UT Health San Antonio, Microbiology & Immunology department pilot project award.

Related publications from the Bunnik lab:
Histone modification analysis reveals common regulators of gene expression in liver and blood stage merozoites of Plasmodium parasites | Ashley Reers et al. | Epigenetics & Chromatin (2023)
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