Evaluation of Intestinal Helminth Modulation of Host Immune Responses

  • Adefunke Ogunkanbi

Student thesis: Phd

Abstract

As one of the neglected tropical diseases (NTDs), soil transmitted helminths are still a major public health problem affecting nearly 2 billion people worldwide. Many studies have demonstrated direct immune regulatory mechanisms by helminths, including lymphocyte hyporesponsiveness, modification of Th1 and Th2-driven cytokine environments and elevation of regulatory cytokine such as TGF-β. Many studies have identified activins, TGF-β functional homologues and TGF-β receptor ligands in parasitic helminths. However, to date no downstream functionality of sequence homologues of the TGF-β superfamily have been identified. In particular, immune regulation by Trichuris species is unexplored, despite their potential as an anti-inflammatory therapy. We hypothesised that T. muris can modulate immune responses by direct induction of host TGF-β and also encoding TGF-β-like ligands as an added immune modulatory strategy. The modulatory potential of T. muris was tested in vivo by assessing the effect of varying doses of embryonated eggs and crude parasite homogenate on host TGF-β release and suppression of inflammatory markers. TGF-β bioactivity in the helminth was investigated using in vitro bioassays and immune cell polarisation approaches on the excretory/secretory (ES) proteins and the homogenate. Finally, using bioinformatics and molecular techniques, TGF-β-like sequences were sequenced from the whole parasite genome and expressed in a bacterial expression system. Chronic T. muris infection drives the release of systemic host TGF-β1 in an infection-dependent manner, independently of the adaptive immune response. In addition, the parasite homogenate and ES components have latent TGF-β activity in vitro which drives Foxp3 expression, inhibits T cell polarisation and can be abrogated by anti- TGF-β antibody and receptor inhibitors. We show for the first time that T. muris has two sequence homologues of the TGF-β superfamily which are evolutionarily conserved within Trichuris species. The parasite sequence shows highest similarity with the mammalian equivalent, at the c-terminal end. In particular, the furin cleavage site and cysteine repeats characteristic of the TGF-β superfamily are conserved. These data demonstrate that nematodes have evolved complementary strategies to modulate the immune response and enhance survival within the host. Furthermore, this innate regulation is sufficient to protect a host during a primary infection. This deepens our understanding of nematode regulation of intestinal inflammation and complements the current paradigm which states that induction of T regulatory cells is central to immune suppression. These data also impact our understanding of how whipworm may regulate inflammation therapeutically.
Date of Award1 Aug 2020
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorJoanne Pennock (Supervisor), Kevin Couper (Supervisor) & Ilaria Russo (Supervisor)

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