Fully Funded PhD: Non-alcoholic fatty liver diseases – towards an innovative alternative therapy using helminth infections or helminth-derived products

Parasitic worms called helminths are the most common infectious agents worldwide with 3.5 billion infected people. Mass deworming treatments aiming to stop the infection spread and control morbidity of those diseases are currently ongoing in endemic countries. However, it has been shown that helminth infections, through their immune-regulatory mechanisms, are epidemiologically associated with lower incidence of metabolic and autoimmune inflammatory disorders, i.e. being infected with worms would protect from type 2 diabetes or non-alcoholic fatty liver disease. An unforeseen consequence of eradicating helminth infections, therefore, may be an increase in immune disorders. Natural killer (NK) cells are immune cells responsible for maintaining the liver homeostasis. Interestingly, it has recently been reported that these cells expand following helminth infection and that the infection prevented early signs of liver dysfunction. This project therefore aims to further investigate hepatic NK cell sub-populations dynamics during helminth infection and identify potential regulatory mechanisms the worms exercise on liver cells. Identifying the signals sent from the worms and that lead to liver protection would be very beneficial in the development of new therapies where worm-derived molecules or drugs could be used to treat populations suffering from immune disorders.

Project aims and objectives

This project is articulated around 3 aims that can be started independently and conducted simultaneously:

Aim 1 - Characterize the liver immune cell populations dynamics and NK cell activation phenotypes in well-characterized experimental schistosomiasis and lymphatic filariasis helminth infection models:

• Obj. 1. In NK-controlled experimental settings
• Obj. 2. In secondary infection experimental settings

We have recently characterized NK cell sub-populations in both helminth infection models. Manipulating the NK cell compartment (using either NK immunodeficient mice, NK cells specific neutralizing antibodies or NK cell adoptive transfers, Obj. 1) or using primed-treated-infected animals Obj. 2) will therefore allow us to investigate the functional interplay between NK cells and effector cells and the degree of innate-memory protection from challenge brought by activated NK cells. Experimental infections will be carried out following published methods and samples of interest will be obtained at key disease development stages time points. The NK cell populations will be analysed primarily via flow cytometry using antibodies panels we have recently validated. Immunohistochemistry (IHC) techniques and Luminex will be used to investigate in situ or systemic markers of NK activation.

Aim 2 – Investigate the potential for helminth excreted/secreted (E/S) molecules to impact host immune cell phenotypes and activation.

We will here benefit from our recently acquired cell sorter to specifically sort immune cell subsets of interest (sub-populations of NK cells, granulocytes) from naïve or infected animals’ tissues and perform in vitro co-culture with worm derived host-facing biofluids (the most well studied of which is E/S contents) and worm tissues. Impact on host cell activation will be assessed through cytokines release content via ELISA and through protein detection/characterization via Western Blot techniques.

Aim 3 – Characterize the NK cell populations dynamics during other experimental helminth infection of interest.

Despite NK cells being well studied since decades, more and more recent studies report/reveal unexpected roles in anti-helminthic infections: from promoting disease tolerance during the invasive stage of an enteric Heligmosomoides polygyrus helminth infection, to NK-mediated improved insulin sensitivity and reduced fat accumulation in the liver in H. polygyrus infected mice and inhibition of NK Cell and IgE-Mediated Signaling in Fasciola hepatica infected animals. Further characterizing NK cell populations dynamics in the context of these helminth infections would provide further understanding on underlying anti-helminthic immunological processes and could provide new therapeutic avenues for the treatment of these diseases or the development of a vaccine.