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Feature: Local evolutionary clues to global vaccine design

Research that could transform our approach to vaccine design and livestock breeding

Autumn 2009

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Research to identify variation in pathogen recognition genes, both within and between mammalian species, could transform our approach to vaccine design, as well as providing a useful tool in livestock breeding programmes to improve genetic resistance against a range of infections.

Veterinary scientists studying a family of genes called toll-like receptors (TLRs) in livestock have identified subtle differences in the way that different animal species have evolved alongside pathogens. Molecules that target TLRs are of interest as new generation ‘adjuvants’ for improved vaccination against infectious disease.

These discoveries will allow researchers to develop or refine vaccines that protect a range of mammalian species against not only bacterial infections caused by Salmonella species and E.coli, but also against viral infections and protozoal infections such as those causing East Coast Fever of livestock and malaria. The work indicates that vaccines could be tailored, by way of strategic TLR agonist adjuvant use, to individual species or even breeds for diseases such as tuberculosis where there is emerging evidence of divergent immune responses.

 

Reading pathogen barcodes

TLRs are one of the most ancient, conserved parts of the immune system that recognise microbes and pathogens by their individual ‘bar code’ of signature components (pathogen-associated molecular patterns) leading to a cascade of cellular responses that ultimately determines the quality or type of immune response generated against the invading pathogen. Because of this, pathogen pattern molecules that activate TLRs are excellent adjuvant molecules for use in vaccines where they can be used strategically to direct host- protective responses against infection.

“Animals have co-evolved with most pathogens for millions of years,” explains Professor Dirk Werling from the Royal Veterinary College (RVC)who is part of a Genesis-Faraday consortium led by Professor David Haig (University of Nottingham), studying animal innate immunity receptors, funded by BBSRC, the Scottish Executive, and Pfizer Ltd. The team also included Drs Tracey Coffey and Jayne Hope from the Institute for Animal Health, and Drs Liz Glass and Oliver Jann from the Roslin Institute.

“We compared TLR gene sequences across a range of mammalian species. We have found evidence that animal immune systems have evolved to recognise pathogens not only in a species-specific manner, but also, pathogens in distinct geographical locations,” says Werling. “In other words, it appears that the local microbial environment drives receptor-binding domain selection in different animal species. Our findings may help to explain why some species/breeds react to a given pathogen or just seem to ignore it. Even more interestingly, our findings could potentially help explain the variable success rates of Tuberculosis (TB) vaccination programmes around the world, as well as why Mycobacterium tuberculosis, which causes human TB, fails to cause disease in cattle”.

Breeding for disease resistance

Interestingly, when comparing the same TLR from different species, and even within different breeds of cattle, the team found a number of potential pathogen recognition sites that differed by only a single amino acid.

“This could have implications for breeding strategies to improve genetic disease resistance in livestock, rather than having to continuously design and develop new antibiotics,” says Werling.

Initial genetic analysis revealed the association of specific TLR sequences with susceptibility to bacterial infections in cattle, such as clinical mastitis and possibly with TB. Interestingly, the same gene-locus seems to be linked with an association with malaria resistance in humans, and other parasitic infections in divergent species such as mouse, sheep and cattle”.

One medicine approach

But as well as highlighting differences between TLR genes from different species, the team have discovered a number of highly conserved sequences involved in pathogen recognition across species. These sequences may be of importance in the understanding of zoonoses such as Salmonellosis or TB. These highly conserved sequences may help scientists to develop adjuvants for new vaccines that show a similar efficacy in both farm animals and humans, especially as there is close contact between these species and a sharing of local infectious agent pools.

The co-evolution of pathogens with their animal hosts and the nature of their components that interact with TLRs should be taken into account during vaccine development. This may be critical in the development of species-dependent and species-independent medicines.

Werling warns, ”In these times of multi-drug resistant bacteria, increased antimicrobial residues in food-products of animal origin, and newly emerging or re-emerging diseases with the potential to cross both geographical and species barriers, we shouldn’t assume that immune responses are going to be the same to any given infectious agent in different species”.

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