Modulation of host immune response by secreted proteins from parasitic worms

Background:

To establish chronic infection, parasitic worms manipulate their mammalian hosts’ immune system. This immune modulation is often mediated by excreted or secreted parasite glycoproteins (ES proteins). Schistosomiasis, caused by parasitic worms of the Schistosoma genus, is a major parasitic disease of huge socio-economic impact in low- and middle-income countries and responsible for 200,000 deaths annually.

Despite treatment with praziquantel, individuals living in endemic areas get repeatedly infected and immune protection from re-infection is slow to develop.

Objectives:

We will use a combination of biochemical, immunological and state-of-the-art imaging approaches to analyse, at the single cell level, host immune responses to ES proteins in the context of primary or repeated Schistosoma mansoni infections.

Novelty:

The molecular mechanisms used by parasitic helminths to subvert their host’s immune response and the effects of repeated infections on immune cell functions remain poorly characterised. Identifying ES proteins with immunomodulatory functions can provide new vaccine targets for the control of schistosomiasis but can also lead to the discovery of new therapeutic strategies for the control of allergic or auto-immune conditions.

Timeliness:

The primary and secondary supervisors have recently developed large libraries of recombinant proteins from S. mansoni larvae and eggs (including ES proteins) for host:pathogen interaction discovery (primary supervisor) and immunological assays (secondary supervisor). The project will use Phenospot, a state-of-the-art technology developed at the host institution (third supervisor), to analyse at the single cell level immune cell responses from naïve hosts or hosts that have undergone single or repeated S.mansoni infections to individual ES protein stimulation.

Experimental Approach:

We will use RNAseq methodologies to identify ES proteins expressed by the parasite at the larval stage of the lifecycle in a murine model of schistosomiasis after single or repeated infections. From this list, we will discover novel immunomodulators promoting parasite survival in pre-armed hosts. We will use an expression cloning approach to identify binding partners for these ES proteins from a genome-wide collection of full-length human surface receptors readily available at the host institution. In parallel, we will use Phenospot to analyse, at the single cell level, the response of selected immune cells populations from naïve murine and human hosts or hosts that have undergone single or repeated S.mansoni infections in response to stimulation by purified recombinant ES proteins. Our analysis of immune cell populations will be partly guided by the identification of host binding partners during the expression cloning step.

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