The role of TLR2 in cutaneous leishmaniasis and as a target for vaccine adjuvants

Halliday, Alice
The role of TLR2 in cutaneous leishmaniasis and as a target for vaccine adjuvants. Doctor of Philosophy thesis, University of Liverpool.

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After the introduction of clean water, vaccination is thought to be the most effective public health tool ever introduced, responsible for preventing millions of cases of disease, disability and death each year. Unfortunately there remain a number of important human diseases for which we have no vaccine, particularly parasitic diseases, such as leishmaniasis, which primarily affect poor communities in tropical regions. There are many complex reasons why we have failed to develop effective vaccines for parasitic diseases, but there is hope that with our improved understanding of the immune system alongside the development of a new generation of vaccines, we will soon develop new vaccines which are effective enough to prevent such diseases. Toll-like receptors (TLRs) are major targets for adjuvants and have been shown to be crucial for defence against a number of infections. TLR2 recognises bacterial lipopeptides in a heterodimer with either TLR1 or TLR6, and its function has been linked to protection against various bacterial infections and to the efficacy of the BCG vaccine. TLR2 has been shown to recognise surface glycoconjugates of Leishmania parasites in vitro, particularly lipophosphoglycan (LPG). In this study, in vivo experimental infections show that TLR2 has a protective role in controlling cutaneous leishmaniasis (CL), as shown by increased lesion sizes and parasite burdens in TLR2-/- mice infected with L. major and L. mexicana. Furthermore, it appears that LPG is not the major mediator of TLR2 activation during infection with L. mexicana, as parasites lacking LPG also resulted in exacerbated disease in TLR2-/- mice. Mice lacking TLR2 co-receptors TLR1 and TLR6 did not show increased susceptibility to infection, suggesting either mono-TLR2 function or alternative co-receptor involvement. Infected TLR2-/- mice show a skewed Th2 immune response to Leishmania, as demonstrated by elevated IL-4, IL-13 and IL-10 production by draining lymph node (DLN) cells in response to antigen. These results suggest that TLR2 is involved in promoting protective immune responses to Leishmania parasites during primary infection in vivo, and is a potential target for protective and therapeutic vaccine adjuvants. Paradoxically, however, TLR2-targeting lipopeptides Pam2 and Pam3 were ineffective adjuvants for use in a whole-cell vaccine to protect against CL, as whole-cell autoclaved L. major (ALM) vaccines containing lipopeptides resulted in exacerbated disease upon challenge when compared to unvaccinated controls and in contrast to effective vaccination when CpG adjuvants were used. The ratio of antigen specific IgG1:IgG2c antibody isotypes, which is a marker of the type of adaptive immune response (Th1 or Th2), was elevated in mice that received vaccines containing lipopeptide adjuvants, suggesting that these adjuvants drive non-protective Th2 responses to Leishmania. In a Th2-dependent vaccine model using Brugia malayi, the use of Pam2 as an adjuvant resulted in an enhanced protective phenotype with similar efficacy to the Th2-driving adjuvant Alum. Thus, in the context of CL infection TLR2 has a protective role in late-stage primary infections with L. major and L. mexicana, yet when targeted with lipopeptide adjuvants in whole-cell vaccines promotes exacerbated disease in challenge infections, through driving Th2 immune responses. Lipopeptides that target TLR2, such as Pam2, are therefore more appropriate for use as adjuvants in vaccines where Th2 protective immunity is required.

Item Type: Thesis (Doctor of Philosophy)
Additional Information: Date: 2013-06 (completed)
Subjects: ?? RC ??
Divisions: Faculty of Health and Life Sciences
Depositing User: Symplectic Admin
Date Deposited: 11 Feb 2014 15:44
Last Modified: 16 Dec 2022 04:41
DOI: 10.17638/00014193
  • Taylor, Mark
  • Craig, Alister