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NK receptors and disease

Periodic Reporting for period 2 - KIRANDIS (NK receptors and disease)

Reporting period: 2018-04-01 to 2019-09-30

Natural Killer (NK) cells are important for immunity to viruses and other pathogens. The receptors on NK cells vary between different individuals and, as a consequence, some people are more susceptible to infection. On the other hand, the variation may result in differences in chronic disease, such as autoimmunity, as well as reproductive syndromes such as pre-eclampsia. The behaviour of NK cells is controlled by a large number of different cell surface receptors, encoded in a region on chromosome 19. Some of these receptors, especially KIR, are highly variable in gene number and allele sequence in different individuals. Many of them interact with HLA class I molecules (the proteins responsible for different tissue types), which are also highly variable. The problem we are addressing is: how do receptors on NK cells interact with their partners, including HLA molecules, on other cells and how can this be exploited to combat disease? This is important for society as it impacts on a number of diseases, including: Haemopoietic stem cell (bone marrow) transplantation, infection, pre-eclampsia and pregnancy disorders, cancer. To explore this we have three main objectives. First, we will study how variation in the receptors influences viral infection and disease course. Secondly, we will investigate the mechanisms viruses use to evade immune recognition. To approach this we have explored interaction of human cytomegalovirus (CMV) with the receptors we are studying. Finally, we wish to identify novel partners for NK receptor. We have evidence that certain viruses interact with some of the receptors in order to evade immune recognition and we are attempting to identify the specific viral proteins that mediate this.
In relation to the 3 objectives:

1. How does variation in LRC molecules influence viral infection and disease course?
To approach this aim we have developed novel methods to type the receptors in different people, including Next Generation Sequencing. We have assembled large panels of DNA from disease patients and matched controls. By typing these samples for the receptors we are exploring their relationship with disease we hope to determine how they influence susceptibility.

James Traherne has visited Peter Parham and Paul Norman in Stanford and has imported advanced methods for molecular typing of different individuals. This has revolutionised our ability to track specific differences in the genes. We are using this to investigate a number of health implications. For instance, we are typing alleles in Uganda with pre-eclampsia to understand how the receptors influence the high rate of this condition in Africa. This work will be presented at the next KIR workshop in Italy, October 2018).

2. Investigation of mechanisms viruses use to evade NK cells.
To approach this we have explored interaction of human cytomegalovirus with receptors. Some of this work has now been published. We are pursuing it further by recruitment of a postdoctoral researcher Mumtaz Naiyer, from Salim Khakoo's laboratory. Mumtaz was first author on a publication from his laboratory in Southampton showing how viral peptides influence receptor recognition:

3. Identification of novel ligands for NK receptors
We have evidence that CMV also interacts with other receptors and we are attempting to identify the specific viral protein that mediates this.
The gene capture and NGS sequencing of KIR has been extremely successful and is state-of-the-art for this work.