[Expired] PhD – The role of metal ions during hist-pathogen interactions

The aim of this thesis is to gain a better understanding of this mechanism linked to zinc toxicity and to improve the innate immunity of livestock and humans.

Message: You will join the MiMoSa (Microbiota, Monogastrics and Salmonella) team which consists of experts in Salmonella pathogenicity and host-pathogen interactions. The position is available for 36 months.

Background and project description: Salmonella is a major source of zoonotic infection, mainly through food contamination linked to eggs and meat from chicken and pork (1). In the host, these infections lead to the recruitment and the activation of macrophages: one of the first immune cells to fight bacterial infections that use a broad arsenal to contain and eliminate pathogens (2). Unfortunately, Salmonella has evolved to survive in host cells. It can remain quiescent in macrophages and use them as a reservoir and as a protection against antibiotics. Thus, it is paramount to identify new pathways that we could modulate to enhance the macrophage antimicrobial response. We have recently characterised a new antimicrobial response in macrophages linked to nutritional immunity that employs metal ions (e.g zinc) toxification and/or starvation to eradicate bacterial infection (3-5). The mechanism still needs to be fully characterised in order to modulate and enhance this antibacterial response.

Objectives: During this project, you will 1) identify the list of critical genes that allow Salmonella to resist and escape zinc toxicity in the host cell; 2) characterise how the zinc-dependent antimicrobial response is driven in the host (in particular in chickens); 3) and contribute to the development of new tools to study zinc toxicity in host cells. The aim of this thesis is therefore to gain a better understanding of this mechanism linked to zinc toxicity and to improve the innate immunity of livestock and humans.

You will be responsible for:
– Identifying the critical genes in the zinc resistance and escape mechanism, using RNA-seq, Tn-Seq analysis and live confocal imaging.
– Characterising the zinc response in different cell types and host species – in particular in chicken, a known asymptomatic carrier of Salmonella.
– Participating to the identification of potential inhibitors for host zinc transporters to help modulate the host antimicrobial response.

You will be supervised by:
– Ronan Kapetanovic, PhD, DR (he/him) – Expert in host-pathogen interaction, macrophages, antimicrobial response
– Isabelle Virlogeux-Payant, PhD, DR (she/her) – Expert in bacteriology and the virulence mechanisms of Salmonella, especially the mechanisms of their interaction with host cells.

References:
1. Coburn B, Grassl GA, Finlay BB: Salmonella, the host and disease: a brief review. Immunol Cell Biol 2007, 85(2):112-118.
2. Stocks CJ, Schembri MA, Sweet MJ, Kapetanovic R: For when bacterial infections persist: Toll-like receptor-inducible direct antimicrobial pathways in macrophages. J Leukoc Biol 2018, 103(1):35-51.
3. von Pein JB, Stocks CJ, Schembri MA, Kapetanovic R, Sweet MJ: An alloy of zinc and innate immunity: Galvanising host defence against infection. Cell Microbiol 2021, 23(1):e13268.
4. Kapetanovic R, Bokil NJ, Achard ME, Ong CL, Peters KM, Stocks CJ, Phan MD, Monteleone M, Schroder K, Irvine KM et al: Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages. FASEB J 2016, 30(5):1901-1912.
5. Stocks CJ, Phan MD, Achard MES, Nhu NTK, Condon ND, Gawthorne JA, Lo AW, Peters KM, McEwan AG, Kapetanovic R et al: Uropathogenic Escherichia coli employs both evasion and resistance to subvert innate immune-mediated zinc toxicity for dissemination. Proc Natl Acad Sci U S A 2019, 116(13):6341-6350.

Training and skills
– Recommended training: Master 2 (Bac +5) in Immunology or Bacteriology
– Appreciated experience: Previous work in BSL2 with pathogen(s), skills in bacteriology and cell culture, experience in bioinformatics would be a plus, ability to work successfully in a collaborative and inclusive environment.
– Skills sought: curious, assiduous, ability to set up and perform well designed experiments, good presentation skills.

Web: https://jobs.inrae.fr/en/ot-21883