A human receptor screening resource for host-pathogen interactions

Infectious agents such as viruses, bacteria, fungi, and parasites cause disease in humans resulting in an enormous humanitarian burden and huge economic costs throughout the world. Direct interactions between the molecules displayed on the surface of our cells and pathogens are usually the first point of contact during an infection and are particularly important to understand how the infection will progress, and how cells of our immune systems will react. Crucially, understanding the molecules that are involved in the initial stages of infection can provide rational pathways to develop new therapeutic strategies and vaccines. Despite their medical importance, detecting interactions between host and pathogen cell surface molecules is challenging because of their specialised biochemical nature; consequently, studying this class of protein interaction remains an important, but relatively underexplored area of science.

Over the last decade, we have developed specialised techniques to investigate these receptors and how they interact with other molecules. At the core of these methods is the creation of libraries containing several hundred different molecules that represent the pertinent external regions of human receptors that are much easier to work with experimentally. Our research has shown that these protein libraries can be used to answer important biological questions in many different fields of research but have been especially useful to detect host-pathogen interactions.

So far, we have compiled a library that represents just under half of all the known human receptors representing a very valuable - although currently incomplete - resource. We know from frequent unsolicited requests from other scientists that there is a latent demand for access to this receptor library; however, producing these proteins is resource intensive so that supporting individual projects on an ad hoc basis becomes economically unviable. To address this, we are proposing to establish partnerships with UK research centres with world-leading expertise in pathogenic viruses, bacteria, fungi and parasites to create a centralised research infrastructure to identify host-pathogen interactions. To widen the overall utility of the library, we will obtain the missing molecules to make a comprehensive set of human receptors. We also want to ensure that this platform becomes a long-standing research infrastructure and so an important objective is to transition the platform into a self-sustaining entity that recovers running costs on a fee-for-service model.

If realised, these partnerships would create a national research infrastructure in the UK that can be used by scientists from many different areas of biomedical research. Importantly, there are no similar resources that exist in the UK or the rest of the world that are openly accessible to academic research laboratories meaning this resource would immediately create research opportunities that would not otherwise exist.

We envisage that this technical platform will facilitate basic discoveries that could improve the quality of peoples' lives including discovering human receptors for viruses and thereby assess their potential to cause future pandemics and identify targets for developing new vaccines.

Extracellular interactions between host receptors and pathogen ligands play crucial roles during infection including subverting immunity and establishing cellular tropism. Despite their importance, detecting these interactions is difficult because receptor proteins are amphipathic making them hard to biochemically manipulate. This has created an unmet need to develop methods to identify these interactions. The extracellular binding function of receptors whose external regions are composed of a contiguous polypeptide can be preserved if expressed as soluble recombinant molecules in mammalian cells thereby making them experimentally tractable. Libraries of these proteins can be used to identify host-pathogen interactions, but this approach is not used because compiling a large library of receptor ectodomains would be too costly for individual projects or laboratories.

Here, we will create partnerships to build a unique screening platform to identify interactions between host receptors and pathogen ligands. By centralising the platform, costs will be significantly reduced making it accessible to many researchers and create new opportunities.
Specific objectives are:

1) extend the collection of protein expression plasmids by 920 to create a resource of 1746 receptors that will be made openly accessible to the global biomedical community by depositing them in Addgene.

2) host-pathogen interactions will be identified through partnerships established with research centres that have world-leading expertise in viral, fungal, bacterial and parasite pathogens. These interactions will provide preliminary data that will seed further funding applications into the molecular basis of infectious diseases.

3) the receptor platform has applications beyond detecting host-pathogen interactions and we are confident that there will be sufficient demand from the biomedical community to ensure the longevity of the infrastructure by supporting it on a fee-for-service model.