Exploring host-immune-microbial interactions during intestinal schistosomiasis

Abstract

Schistosomes are extraordinarily successful parasites and experts of immune calibration. Like other helminths, schistosomes have evolved sophisticated mechanisms to circumvent and modulate immune responses, ultimately permitting their long-term persistence within the host. This recalibration reflects the spectrum of immunomodulatory molecules produced by schistosomes, alongside the host’s reparative response to parasite-inflicted damage. Importantly, as schistosome eggs cause considerable destruction to the host as they rupture the intestinal wall, it is possible that intestinally-derived signals, including those from the microbiota, may contribute to the immune responses found during schistosomiasis. In the work detailed in thesis, we attempt to dissect the involvement of parasite, host, and microbial factors in the instruction of schistosome associated Type 2 and Regulatory cell networks. First, we systematically characterise immune profiles across the course of conventional egg producing infections, providing a concise narrative of how schistosomiasis associated immune profiles evolve over time in effector and priming sites. Here, though the depletion of CD11c+ cells at peak stages of disease, we reveal a role for CD11c+ DCs in the maintenance of S. mansoni elicited Type 2 immunity. Next, by using a combination of high vs low dose, and egg producing vs non egg producing infections, we show elevated intestinal permeability during chronic and high dose egg producing infections, with hints towards enhanced bacterial translocation. Infection patency evoked a Type 2 dominated immune response in the mesenteric lymph nodes and colon that coincided with significant intestinal microbiome alterations. Significantly, through the use of germ free mice and faecal transplants, we provide evidence that the schistosome infection associated microbiota can influence the character of host Immunity. Moving on from the intestine and Type 2 immunity, we next sought to better define the signals endorsing schistosome elicited Regulatory B cell (Breg) and T cell (Treg) expansion. Through the interrogation of Type-I signalling, we show IFN-I to assist in murine Breg generation in an in vitro but not in vivo setting. Finally, we show chronic egg-producing and non-egg producing S. mansoni infections to expand phenotypically distinct Treg and Breg and populations, with microbiotas from these mice capable of modulating the severity of experimental allergy. Together, our data elevates the mechanistic understanding of parasite-host-microbial relations and provides a strong platform for the future study of schistosome or microbial factors in the modulation of inflammatory disease.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Grencis (Supervisor) & Andrew MacDonald (Supervisor)