Multiparameter tissue landscapes: shaping neutrophil functional states

PROJECT OVERVIEW

Neutrophils represent a major arm of the innate immune defence system, with a long- held view of them being transcriptionally inactive, fast responders, mobilised in response to microbial and tissue insults. Recent developments in the field have changed this perception and firmly positioned neutrophils as transcriptionally active cells with the ability to adapt their transcriptional program. Our recent findings demonstrate that, despite limited residence times in tissues, neutrophils can tailor their properties to support organ homeostasis and mount tissue specific and transcriptionally regulated inflammatory response^1,2. Importantly, in inflammation neutrophils are presented as functionally, morphologically and behaviourally heterogeneous cells in circulation and tissue³. Our central research question is: How do distinct tissue niches shape neutrophil functional states, and can this be leveraged to ameliorate immunopathology?

This project aims to uncover how distinct tissue environments shape neutrophil gene expression programs and functional states, with a particular focus on immunopathology. Building on our recently generated single-cell RNA sequencing (scRNA-seq) datasets from inflamed joint and colon tissues (unpublished), we will define common and tissue-specific neutrophil signatures and identify the transcriptional networks underlying their adaptation to regional niches. By integrating these datasets with spatial transcriptomic and high-resolution imaging data, we will explore how the geography of inflammation, including the spatial distribution of neutrophils and their interactions with tissue-resident immune and stromal cells, orchestrates neutrophil functional heterogeneity.

A key component of the project is to map the temporal and spatial dynamics of neutrophil recruitment and adaptation in tissue. We will apply advanced mathematical and spatial modelling to analyse multiparameter tissue landscapes and infer how spatially constrained signals influence transcriptional regulatory networks using the recently developed Multiscale Spatial Analysis toolbox (MuSpAn: https://www.muspan.co.uk/). Lattice Light Sheet (LLS) microscopy will be used to visualise neutrophil morphology and behaviour in three dimensions, enabling the integration of morphological features with transcriptomic identity using machine learning and topological data analysis⁴. This multimodal approach will allow us to identify spatially restricted transcriptional states and how these relate to disease-driving or resolving neutrophil phenotypes.

This work will capitalise on our extensive transcriptomic and imaging datasets, as well as unique genetic models². The results will enhance our understanding of the spatial and transcriptional logic of neutrophil plasticity and contribute to identifying new therapeutic strategies targeting pathogenic neutrophil states in tissue-specific inflammatory diseases⁵

KEYWORDS

Neutrophils, transcriptional regulators, computational genomics/epigenomics, spatial transcriptomics, mathematical modelling

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre and is housed in a state-of-the-art research facility. Training will be provided in a wide range of functional genomics approaches (e.g. RNA-Seq, ATAC-Seq, ChIP-Seq etc), immunological (cell isolation, tissue culture, FACS), and imaging (immunofluorescence on tissue sections) approaches, as well as cutting edge single cell platforms (10x, Nanostring GeoMx, Nanostring CosMx) and computational pipelines. Recently developed novel in vivo models of inflammatory diseases will be extensively used and new models will be generated.  A core curriculum of lectures will be taken in the first term to provide a strong foundation across a broad range of subjects, including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. The student will attend weekly seminars within the department and those relevant in the wider University. They will present their research regularly to the department and the Genomics of Inflammation group, and at the Computational Genomics Forum. They will also attend external conferences at which they will present their research to a global audience.  The student will also have the opportunity to work closely with members of the Wolfson Centre for Mathematical Biology at the Mathematical Institute, University of Oxford, and to further broaden their theoretical knowledge by attending lecture courses in mathematical biology, statistics and related subjects. 

KEY PUBLICATIONS

(1)        Ballesteros I, Rubio-Ponce A, Genua M, …, Udalova IA, Ng LG, Ostuni R, Hidalgo A. Co-option of Neutrophil Fates by Tissue Environments. Cell. 2020 Nov 25;183(5):1282-1297.e18.

(2)        Khoyratty T*, Ai Z*, Ballesteros I, Mathie S, …, Hidalgo A, Udalova IA. Distinct transcription factor networks control neutrophil-driven inflammation. Nature Immunology, 2021 Sep;22(9):1093-1106.

(3)        Wang L, Luqmani R, Udalova IA. The role of neutrophils in rheumatic disease-associated vascular inflammation. Nature Reviews Rheumatology. 2022 Mar;18(3):158-170.

(4)        L Marsh, FY. Zhou, X Qin, X Lu, HM Byrne, HA Harrington (2024). Detecting Temporal shape changes with the Euler Characteristic Transform. Transactions of Mathematics and Its Applications 2024, 8(2): tnae002.

 (5)       Devaprasad A, Radstake TRDJ, Pandit A. Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies. Frontiers in Immunology. 2021 May 24;12:669400. 

THEMES

Immunology; Computational Genomics; Spatial transcriptomics; Mathematical modelling

CONTACT INFORMATION OF ALL SUPERVISORS

Prof Irina Udalova: irina.udalova@kennedy.ox.ac.uk

Prof Helen Byrne: helen.byrne@maths.ox.ac.uk

Dr Abhinandan Devaprasad: abhinandan.devaprasad@kennedy.ox.ac.uk