Cambridge Institute for Medical Research

Professor Paul Lehner

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Viral immune evasion mechanisms

We are interested in viral evasion of the immune system. As the ultimate intracellular parasites, viruses target the host cellular machinery to enable their replication and avoid elimination by the immune system. Our research goals and themes are to use functional genetic and proteomic technologies to identify novel cellular receptors manipulated by viruses, understand why these receptors are targeted and elucidate the mechanisms used by viruses to manipulate the cellular immunoreceptors.

Why is the study of viral evasion mechanisms of interest? Identifying host cellular receptors targeted by viruses is important for several reasons: Viruses are assiduous cell biologists. Studying the critical host receptors targeted by viruses and understanding the mechanisms they use to manipulate cellular processes provides unique insights into fundamental cell biological pathways, teaches us about viral pathogenesis and has the capacity to offer novel therapeutic approaches, for instance by targeting these newly identified receptors.

Viral regulation of cell surface receptors:
Cell surface receptors are modulated by all intracellular pathogens. Our work on viral evasion of the MHC class I antigen presentation pathway has driven our interest in the role of ubiquitin in immunoreceptor regulation. We identified the K3 and K5 viral ubiquitin E3 ligases which ubiquitinate, downregulate and degrade cell surface MHC I molecules via the endolysosomal pathway. A major goal has been to develop unbiased methods to identify cell surface receptors up- or downregulated by viruses. Using SILAC-based proteomics we can differentially analyse >600 plasma membrane proteins, and therefore identify those receptors whose expression is altered by viruses. This technology has identified immune evasion as well as metabolic receptors whose expression is dramatically altered following infection.

Defining the mechanism of action of these novel receptors:
Using genetic, biochemical and cell biological approaches we then determine how newly identified cell surface proteins are compromised by intracellular pathogens. For example, our siRNA screens identified novel E3 ligases, such as TRC8, involved in receptor regulation as well as their physiological substrates. We use traditional biochemical as well as novel insertional mutagenesis-based genetic screens to identify the critical pathway components required for immunoreceptor regulation.