Maizels, Rick

Gally, David

Reynolds, Lisa Anne

Wellcome Trust

2013-10-22T13:39:15Z

2013-10-22T13:39:15Z

2013-06-29

The mammalian intestinal tract is highly colonised with a diverse bacterial microbiota. The importance of this bacterial presence is now recognised; these bacteria contribute both to the nutritional status of their hosts and are required for the development of a competent immune system. In addition, the composition of the microbiota is likely important in influencing how the immune system reacts to antigens, as the presence of specific bacterial species can promote differentiation of T cells towards specific effector or regulatory fates. Though the ability of the microbiota to influence infections with bacterial and viral agents has been reported, whether the microbiota can affect a parasitic infection has not yet been described. It is likely, due to millions of years of co-evolution within mammalian hosts, that helminths have co-opted mechanisms of the microbiota to manipulate the host’s immune system, in order to promote their own survival. In this thesis, the immune parameters required for expulsion of a primary infection with the murine gastrointestinal helminth parasite Heligmosomoides polygyrus are examined, and whether the microflora influence these parameters in order to modulate susceptibility is explored. Firstly, a multiparameter analysis of H. polygyrus infection was performed in two mouse strains which differ in susceptibility to a primary infection, to identify both immune factors and microbial populations which correlate with susceptibility to infection. BALB/c mice exhibited a stronger T helper (Th)2-type response to H. polygyrus excretory-secretory antigen (HES), produced high numbers of intestinal granulomas following infection and were better able to expel H. polygyrus, whereas the more susceptible C57BL/6 strain produced higher levels of inflammatory Th1 cytokines in response to HES. High levels of duodenal Lactobacillus/Lactococcus species positively correlated with H. polygyrus persistence within the BALB/c host, as did high levels of Enterobacteriaceae in the C57BL/6 host. Furthermore, the abundance of both of these bacterial groups was elevated in H. polygyrus-infected C57BL/6 mice compared to naïve controls, and mice given antibiotic treatment to diminish these groups were rendered more resistant to H. polygyrus. Infection persistence was prolonged in BALB/c mice which were administered the single species Lactobacillus taiwanensis, a normal component of the microbiota. Next, the impact of a loss of microbiota signalling by immune cells during H. polygyrus infection was examined, through the use of Toll-like receptor (TLR)- and TLR adaptor protein-deficient mice. MyD88-/- mice were more resistant to H. polygyrus than wildtype (Wt) C57BL/6 mice and exhibited increased granuloma formation: phenotypes which were not recapitulated by individual deficiencies in TLR2, TLR4, TLR5 or TLR9, and not seen in TRIF-/- mice. When MyD88-/- mice were additionally deficient in TRIF, the increased granuloma formation phenotype of MyD88-/- mice was lost. Whether MyD88 controls susceptibility to H. polygyrus infection via a TLR-independent mechanism, and how MyD88 and TRIF antagonistically contribute to granuloma formation remains to be resolved. Finally, the importance of TGF-β signalling during H. polygyrus infection was examined, using mice deficient in TGF-β signalling specifically in T cells (TGF-βRII DN mice). These mice were more susceptible to H. polygyrus than Wt C57BL/6 mice, which was explained by an attenuated Th2 response to infection accompanied by exuberant IFN-γ production. The increased susceptibility to H. polygyrus was lost in TGF-βRII DN IFN-γ-/-mice, in which Th2 responsiveness was partly restored. These data highlight the importance of both immune components, particularly IFN-γ, which promotes susceptibility, and the presence of specific intestinal bacterial populations in controlling the persistence of a primary H. polygyrus infection.

http://hdl.handle.net/1842/7960

en

The University of Edinburgh

Maizels, RM, Hewitson, JP, Murray, J, Harcus, YM, Dayer, B, Filbey, KJ, Grainger, JR, McSorley, HJ, Reynolds, LA, and Smith, KA. 2012. Immune modulation and modulators in Heligmosomoides polygyrus infection. Exp Parasitol. 132: 76-89.

Reynolds, LA and Maizels, RM. 2012. Cutting Edge: In the Absence of TGF-β Signaling in T Cells, Fewer CD103+ Regulatory T Cells Develop, but Exuberant IFN-γ Production Renders Mice More Susceptible to Helminth Infection. J Immunol. 189: 1113-7.

Reynolds, LA, Filbey, KJ, and Maizels, RM. 2012. Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus. Semin Immunopathol. 34: 829-846.

helminth parasite

Heligmosomoides polygyrus

commensal bacteria

The immune response and the intestinal microbiota in control of susceptibility to Heligmosomoides polygyrus

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy