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Title: Isolates of Trichuris muris : host immune response and characterisation of secreted parasite antigens
Author: Johnston, Claire
ISNI:       0000 0004 2682 8893
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2005
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Gastrointestinal helminths infect over 1 billion people worldwide. While rarely causing death, intestinal helminths cause high morbidity, especially in children and result in huge economic losses each year. While antihelminthics have proven effective, in endemic areas reinfection is common and the emergence of antihelminthic resistance is a major concern. The murine intestinal nematode, Trichuris muris has been utilised as a good model for the human parasite, T. trichiura for the past 45 years and has yielded much evidence of the immune response to this caecal-dwelling nematode. Studies of the immune response to T. muris have mainly been conducted using the E isolate. Host resistance to T. muris relies upon the development of a Th2 response while susceptibility correlates with a Th1 response. In the present work, studies were conducted using the J and S isolates and the conventionally-studied E isolate. Firstly, the phylogenetic relationship between the E, J and S isolates was explored by comparing internal transcribed spacer (ITS) 2 sequences between the isolates and to other ITS2 sequences from other Trichuris species. These analyses revealed the isolates to be extremely similar at this level. Following this, the immune response elicited by the E, J and S isolates of T. muris in male AKR, C57BL/6 and BALB/c mice was characterised. In BALB/c mice, all isolates were expelled and was, with all three isolates, associated with an elevated Th2 response. In contrast, all three isolates persisted to chronicity in AKR mice but the E and S isolate elicited significantly higher IL-12 while levels in J-infected mice were equivalent to naïve. Serum MMCP-1 was significantly higher in J and E-infected mice compared with S-infected mice. Interestingly, differential worm expulsion kinetics occurred in the C57BL/6 mouse strain, with the E and J isolate expelled by d 35 p.i. but the S isolate was retained to chronicity. Furthermore, levels of Th2 cytokines were markedly lower in S-infected mice while type 1 cytokines IL-12 and IFN-γ were raised in all infected groups. The lower Th2 response in S-infected mice was reflected in a lower goblet cell hyperplasia and a lower mastocytosis and eosinophilia. IgG1 was equally raised while IgG2a was lowest in J-infected mice. In contrast, female C57BL/6 mice were able to mount a Th2 response against the S isolate and expel most worms by d 35 p.i. Furthermore, survival of the S isolate is dependent upon MyD88 thus MyD88 KO mice expelled the S isolate in a Th2-dependent manner. To begin to address the mechanism underlying S persistence, the effects of isolate-specific E/S on DC were examined. Interestingly, CD 1lc+ DC from C57BL/6 mice upregulated MHC II expression when stimulated with E and J E/S but did not with S E/S. Western blots showed parasite-specific E/S to be differentially recognised by mouse strain-specific antibody, with strong recognition of low molecular weight antigens being associated with susceptibility. Furthermore, E/S zymography revealed protease activity at approximately 20 kDa which was greatest in S isolate E/S. Inhibition studies showed differential protease activity between isolate specific E/S but all exhibited serine protease activity. Overall, these studies enhanced previous understanding of the immune response to T. muris as a whole thus highlighting the relevance parasite isolates have in parasite immunology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available