Mononuclear phagocytes in the intestine, including macrophages and dendritic cells, are specialised to sample their environment for foreign antigens and pathogens. After acquiring antigens these cells then travel to the gut associated lymphoid tissues (GALT) and mesenteric lymph nodes where they present the antigens to lymphocytes to initiate an immune response. Exciting data show that macrophages within the gut mucosa also closely interact with the enteric nerves within the gut wall. Importantly, the mucosal macrophages and enteric nerves communicate with each other to help control important physiological functions (1,2). For example, the macrophages secrete factors which stimulate the nerves to modulate gut motility (peristalsis). The enteric nerves in turn promote macrophage homeostasis by secreting the macrophage growth factor, CSF1. This mucosal macrophage-enteric nerve cross-talk is highly responsive to stimuli from the gut microbiota which can modulate the activation status of the macrophages and enteric nerves, and by doing so, affect gut motility. Many pathogen infections are orally acquired, but whether they influence this macrophage-enteric nerve cross-talk is unknown and will be studied here. An understanding of the effects of pathogens on macrophage-nerve crosstalk is essential to identify the factors that modulate gut homeostasis, and identify novel targets for therapeutic intervention.
This project will address the following main objectives:
1-Characterise the distribution of, and associations between, enteric nerves and macrophages throughout the entire intestine
2-Determine the influence of oral pathogen infection (eg: bacteria and helminths) on the distribution and status of mucosal macrophages and enteric nerves, and the effects this has on gut motility
Prion diseases are infectious neurological diseases which can be acquired through oral consumption of contaminated food or pasture. After oral exposure, the prions first accumulate within the GALT before spreading to the brain (termed, neuroinvasion) where they cause neurodegeneration. Our studies show that mononuclear phagocytes also play an important role in the initial uptake and transport of prions from the gut lumen to GALT (3). The prions then spread to the brain via the enteric nerves in the gut wall, but how they first infect the enteric nerves is not known. Since future prion disease outbreaks are likely to be orally-acquired, a thorough analysis of the factors that influence susceptibility to orally-acquired prion diseases will help identify the factors which enhance disease susceptibility, and identify novel intervention targets. The close association of macrophages with enteric nerves suggests that macrophages may play an important role in this neuroinvasion phase. The third aim of this project will study this important missing link.
3-Determine the role of macrophages in prion neuroinvasion from the intestine
Training: This exciting multidisciplinary project will enable the student to gain important transferable skills in distinct scientific disciplines, including: in vivo mucosal immunology, macrophage biology, host-pathogen interactions, bioimaging and transcriptomics. The project will involve a significant in vivo component using transgenic/knockout mice, gastrointestinal infections and in vivo bioimaging. Many laboratory techniques including in situ hybridisation, immunohistochemistry, transcriptomics, cell-culture, flow-cytometry etc. will be used. Extensive training in bioimaging and related morphometric analyses, bioinformatics and statistical analyses, will also be provided.
1-Muller PA, Kosco B., Rajani GM et al. (2014) Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300-313.
2-Gabanyi I, Muller P A, Feighery L, Oliveira T Y, Costa-Pinto F A, et al. (2016) Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378-391.
3-Bradford B M, Reizis B. & Mabbott NA (2017) Oral prion disease pathogenesis is impeded in the specific absence of CXCR5-expressing dendritic cells. Journal of Virology 91, e00124-17.