Talk Title: “Transmission-blocking nanobodies targeting Plasmodium falciparum fertilisation antigens.”
Abstract: Malaria parasite fertilisation occurs in the midgut of female Anopheles mosquitoes. By blocking fertilisation in the mosquito, we can stop transmission of the malaria parasite. I will present work on using nanobodies to block malaria parasite transmission. In particular, I have generated nanobodies targeting fertilisation antigen Pfs48/45, one of the leading transmission-blocking vaccine candidates. I have used biochemical and structural approaches to characterise nanobody interactions and examined the ability of nanobodies block fertilisation of the malaria parasite using standard membrane feeding assays with Anopheles stephensi. This work demonstrates the potential of nanobodies as a versatile antibody format that can reduce malaria transmission.
Ashton Kelly Bio:
Ashton is a Postdoctoral research fellow at the Institute for Molecular Biosciences at The University of Queensland, in Professor Denise Doolan’s lab. Her work over the last few years has focussed on understanding the unique molecular signatures at a single-cell and bulk proteomic and transcriptomic level in the context of blood stage P. falciparum infection. We aimed to understand the variable immune responses between individuals during controlled infections. During her PhD Ashton employed an integrated systems immunology approach—combining mass cytometry, bulk proteomics, and single-cell transcriptomics of sorted natural killer (NK) cells—to identify both pre- and post-infection immune signatures that contribute to these variable host responses. Having successfully established these high-dimensional profiling techniques within our lab, Ashton developed experimental and analytical pipelines that have advanced the understanding of human immune heterogeneity. Ongoing work uses these platforms to explore host-pathogen interactions in Plasmodium infection, with expanding interests in viral co-infections. Outside of the lab Ashton is an awesome rugby union player looking forward to another great season with the UQ Red Heavies!
Title and abstract:
“Understanding the molecular basis of immune heterogeneity in NK cells during controlled infection with P. falciparum”
Malaria, caused by Plasmodium species parasites, remains a significant public health burden across the globe, with infected individuals exhibiting a diverse spectrum of clinical outcomes, ranging from asymptomatic to severe disease. However, the molecular mechanisms underlying immune heterogeneity remain poorly understood. Natural Killer (NK) cells, positioned at the innate-adaptive immune interface, have been implicated in controlling Plasmodium parasite burden, yet the role of specific NK cell subpopulations in malaria remains largely unexplored. In this study we leveraged samples from Controlled Human Malaria Infection (CHMI) trials to investigate NK cell heterogeneity and its association with variable infection outcomes. Individuals were classified as “good” or “bad” responders based on parasite multiplication rate (PMR) following infection. Using a systems immunology approach, we employed single-cell RNA sequencing, single-cell proteomics, and bulk proteomics to characterise distinct NK cell populations and molecular signatures associated with differential immune responses to infection. Our findings revealed distinct NK cell subpopulations at baseline with unique transcriptional and proteomic profiles associated with good or bad responders following infection. scRNA-seq identified highly heterogeneous populations of NK cells, including multiple novel populations within the CD56+CD16+ compartment. Notably, good responders exhibit transcriptional signatures associated with immunoregulatory phenotypes driven by cytokine modulation. Single-cell proteomics further highlighted highly inflammatory NK populations in poor responders across multiple NK cell populations. Additionally, bulk proteomics identified proteins linked to parasite replication and immune function pre- and post-infection. Our findings underscore the critical role of NK cells in malaria immunity and reveal previously unrecognised heterogeneity within this population. Additionally, our study demonstrates the power of multi-omics approaches in dissecting immune responses, particularly within small immune cell populations, providing insights into potential targets for malaria intervention strategies.
Our ASP Online Seminar Series image is created by Thorey Jonsdottir.
