Modelling gastrointestinal co-infection in acute malaria

Supervisors: Dr Alexandre Potocnik (Institute for Immunology and Infection, The University of Edinburgh), Prof. Neil Mabbott

Project description:

A fascinating problem in basic research is the impact of environmental signals on the dynamics of haematopoietic differentiation and the resulting impact on health. We are in particular interested how gut microbiota can crosstalk with the haematopoietic system. One consequence of a severe acute infection is the change from steady-state haematopoiesis to stress-induced emergency myelopoiesis. In order to investigate the impact of gut microbiota on this process we will induce a change of the composition of the microbiota by the addition of another gut resident bacterial species. We plan to investigate the impact of an established gastrointestinal infection by Salmonella typhimurium on an acute infection with malaria in a mouse model. Our aim is to define:

  • Induction of inflammation in the gut and the localisation of the pathogenic bacteria
    We will generate a set of genetically-tagged Salmonella typhimurium substrains to investigate the precise localisation and spreading during a sub-lethal bacterial infection. The genetic tags (red fluorescent protein FP635 in combination with luciferase) will enable to build up a comprehensive map of the intestinal infection allowing longitudinal studies of this process.
  • Effect of gut microbiota on infection
    We will focus on the specific composition of the intestinal microbiota during single infections and co-infections. Advanced microbiom analysis (Microbiomics) will be employed to understand the expected changes of the microbiota. In parallel we will analyse the transcriptom of early myeloid progenitors and precursors in this model.
  • Impact on the initial stages of malaria in this co-infection model
    Our focus will be on the initial stages of malaria and the impact on the stress-induced myelopoiesis during an ongoing infection with S. typhimurium. Of particular interest are the induction of emergency myelopoiesis in the bone marrow and the response of innate and adaptive immunology in the gut mucosa.
  • Integration of datasets
    Our main interest here is to probe the impact of an altered intestinal microbiota on the genetic reprogramming of haematopoiesis during infection. All datasets will be aligned with previously generated datasets of equivalent cell subsets in naïve mice and malaria infected mice. Using advanced bioinformatics we will identify key signalling pathways affected by an altered intestinal microbiota.

This exciting PhD project will employ a variety of techniques in particular: microbiology (generation of genetically-tagged S. typhimurium substrains by CRSPR/Cas9 genome editing, analysis of bacterial microbiota), immunology (analysis of parameters of the immune response; emergence of infection-induced haematopoietic populations), and stem cell biology (Analysis of intestinal stem/progenitor cells, bone marrow haematopoietic progenitors). In addition, we will utilise cutting-edge technology in flow cytometry, imaging (confocal microscopy) and 3D‑image reconstruction. The combination of these technologies provides an ideal environment for interdisciplinary training in a project at the interface of immunology and microbiology.

References:

  1. Belyaev N.N. et al. (2010). Induction of an IL‑7R+c‑Kithi myelolymphoid progenitor critically dependent on IFN-gamma signaling during acute malaria. Nat. Immunol. 11, 477-485.
  2. Villarino N.F. et al. (2016). Composition of the gut microbiota modulates the severity of malaria. Proc. Natl. Acad. Sci. USA 113, 2235-40.

 

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