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Understanding mechanisms and functions of evolutionary divergence in innate immune genes

Discovery Early Career Researcher Award DE130100470

Final Report 2016 (download here)

ARC link

 

Systematic characterization of the involvement of “human-specific” TLR-inducible genes in responses to Gram- negative pathogens. Investigate functions of candidate species-specific immune response genes (zinc and novel genes)

Summary: Depending on their environment, mammals are exposed to different pathogens and display different gene regulation. This environmental pressure can lead the organism to evolve and to become less susceptible to pathogen. By studying the differences in the gene expression pattern, we aimed to identify new antimicrobial pathways that have evolved in certain organisms, such as Salmonella, and that could enhance innate immune response in human and in livestock. Amongst the different targets we found, two genes, differentially regulated upon inflammation between human and mice, showed promising outcomes in term of antimicrobial effects. This project led us to investigate how macrophages can control the concentration of metal ions, in particular zinc, to fight infections. We also found that one deacetylase enzyme gene expression was up-regulated in human compared to mouse and was limiting the anti-bacterial response.

Benefits: this Project expanded our knowledge on the function of genes that play an important role in the response to intracellular pathogens in macrophages. This includes genes involved in zinc toxicity, modulation of IL-1beta release or post-transcriptional modification of key proteins of the immune response. Understanding how to enhance antimicrobial pathways in macrophages by increasing metal ions toxicity or by inhibiting specific molecule via a pharmaceutical approach could be of significance for medical care but also livestock anti-infective treatment. Indeed, my project may benefit the agriculture industry by improving animal welfare and contributing to the control of animal diseases. I expect that results from this project will ultimately lead to new therapeutic approaches to protect livestock and could also lower the systematic use of antibiotics in the farming industry.

 

Outcomes: this Project has contributed into advancing our knowledge of the role of novel genes induced in a human-specific fashion during intracellular pathogen infection. In particular, we have focused our attention on 3 different targets; the zinc transporter SLC39A8, a E3 ligase RNF144B and a histone deacetylase (HDAC) family member. We unveiled new insights on how macrophages used metal ions and Zinc in particular during Salmonella infection and showed that this pathogen has evolved mechanisms to evade the zinc toxicity. We have discovered a new role of RNF144B as a regulator of inflammation in macrophage showing different function in mouse and human. We have also found that some HDACs can also modulate antimicrobial response in macrophages, limiting the intensity of the immune response. Therefore, this discovery could lead to a new therapeutic approach to treat bacterial infections, in particular in the case of multi-drugs resistance microbes. I also participated in the characterisation a novel TLR-inducible protein (SCIMP) in macrophages that shows opposite gene expression between human and mouse. This work lead to a publication in Nature Communications. Finally, collaborative work with colleagues from the Roslin Institute led to the characterisation of horse macrophages and to a comparative mapping of promoters and enhancers from humans, mice and pigs. The data confirmed extensive gain and loss of regulatory elements between species, and the likelihood that pigs provide a better model than mice for human gene regulation and function. This project has also allowed me to gather different mammalian cells that will be used for following work. This will help us in gaining a greater understanding of the regulatory divergence of such genes across multiple species,

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