“Inborn errors of immunity (IEI) have provided many insights into susceptibility to infection and advanced our understanding of human host defense mechanisms. IEI are often associated with autoimmune and inflammatory changes as well, with manifestations that vary considerably from patient to patient. An outstanding challenge for the field, particularly in autosomal dominant forms of IEI, is to explain phenotypic variation and incomplete penetrance in different individuals carrying the same IEI-associated allele.

Normally, cell counts and immunoglobulin levels remain relatively constant over time despite environmental challenges, indicating that the immune system is robust to perturbation. Our hypothesis is that some gene defects, particularly those responsible for autosomal dominant IEIs, compromise immune homeostasis. As a result pathological changes emerge under substantial environmental stressors, of which infection is an obvious and plausible candidate. This mechanism could explain why immunopathology is more common in IEI, while specific manifestations vary according to the burden and nature of infection.

Antigen-driven CD4+ T cell differentiation is associated with several dysfunctional outcomes, including senescence, exhaustion and cytotoxicity. In this project, we will characterise these dysfunctional cellular outcomes using a large dataset obtained from a national cohort of patients with different IEIs. Once we identify pathological changes in cellular differentiation in association with specific gene defects, we will investigate the mechanism linking genotype to cell differentiation in bespoke mouse models in which the orthologous genetic variant has been engineered generated by CRISPR/cas9. By investigating the actions of pathogens in hosts sensitised by genetic defects, we expect to identify mechanisms that might be relevant to patients that do not have single gene defects in immunity.”

“Evolution has produced an arms race between viruses and the cells they infect. Studying this battle provides key insights into cell biology and immunology, as well as the viruses themselves. It may even lead to the development of novel therapeutics. The Matheson lab therefore focuses on two pandemic viruses with a major impact on human health: HIV and SARS-CoV-2.

We have previously used unbiased proteomics to quantify dysregulation of hundreds of proteins and processes in infected cells, and now aim to understand the importance of these targets for both viral pathogenesis and normal cellular physiology. Because HIV regulates numerous cell surface amino acid transporters, we are particularly interested in amino acid metabolism and protein biosynthesis.

Depending on the interests of the student, this project will therefore focus on either (1) an orphan cell surface amino transporter downregulated by SARS-CoV-2 infection of respiratory epithelial cells or (2) an ancient metabolic enzyme regulating ribosomal frame shifting depleted by HIV infection of primary human CD4+ T cells.

In either case, the aims will be to: validate the target in different systems; define the mechanism of viral regulation; determine the functional effects of target depletion in biochemical and cell biological assays; and characterise the impact of target depletion on viral infection. Opportunities will be available to conduct further proteomic screens, perform ribosomal profiling and/or stable isotope-based metabolomics.

The project will provide training in a wide range of molecular and biochemical techniques, whilst allowing the student to explore an important aspect of the host-virus interaction. The Matheson lab is based in the brand new Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), including the largest academic Containment Level 3 (CL3) facility in the UK. The student will be supervised by an experienced postdoc in a friendly, supportive group. ”

“Endogenous viruses, accounting for 15% of our genome, serve as a genetic reservoir from which new genes and regulatory elements can emerge to fulfill essential cellular functions. We study endogenous viruses – particularly evolutionarily divergent ones – to gain insights on how genetic exchange between viruses and their hosts contributes to vital biological processes.

We recently identified Atlas virus, a novel, intact endogenous retrovirus in the human hookworm Ancylostoma ceylanicum with an envelope protein genetically related to GC envelope glycoproteins from phleboviruses. A cryo-EM structure of Atlas GC revealed a class II viral membrane fusion protein fold not previously seen in retroviruses. Atlas GC has the structural hallmarks and biological activities of an active fusion protein. With its preserved biological activities, Atlas GC has the potential to acquire a cellular function. Our work reveals structural plasticity in reverse-transcribing RNA viruses.

This PhD project combines biophysical and cell-based approaches to study endogenous viral proteins with novel cellular functions. We will apply bioinformatic approaches to identify GC orthologs and other virus-derived proteins or transcripts with potential roles in gamete fusion, syncytia formation or other essential cellular functions in vertebrates. We will assess the functions proteins from the HERV-K family of human endogenous retroviruses, for which aberrant expression has been associated with cancer and neurodegeneration. This project will help uncover how endogenous viruses, our genetic dark matter, function in health and disease.

1. Merchant M, Mata CP, Liu Y, Zhai H, Protasio AV, Modis Y (2022) A bioactive phlebovirus-like envelope protein in a hookworm endogenous virus. Sci. Adv. 8:eabj6894
2. Frank JA, Feschotte C (2017) Co-option of endogenous viral sequences for host cell function. Curr Opin Virol 25:81-89″

Our laboratory has recently discovered a new type of unprecedented multi-functional enzyme, conserved from bacteria to man, which challenged fundamental principles of core purine metabolism. This single-pocket enzyme catalyses activities that had so far been thought to be the sole domain of adenosine deaminase (ADA; adenosine + H2O ⇌ inosine + NH3), purine nucleoside phosphorylase (PNP; guanosine/inosine + phosphate ⇌ guanine/hypoxanthine + ribose-1-phosphate) and methylthioadenosine phosphorylase (MTAP; methylthioadenosine + phosphate ⇌ adenine + methylthioribose-1-phosphate) – ubiquitously expressed enzymes present in any form of life that supply purine nucleobases. This new enzyme additionally exhibits adenosine phosphorylase activity (adenosine + phosphate ⇌ adenine + ribose-1-phosphate), an activity which had been considered outrightly absent from eukaryotic metabolism. Genetic loss of function of this enzyme, which we named FAMIN, is the sole known cause of monogenic Still’s disease. Still’s disease is an early-childhood disease and the paradigm of autoinflammation-cum-autoimmunity as it starts with a periodic fever and morphs over weeks into a debilitating arthritis that is thought to be T cell driven. A common variant of FAMIN, for which ~6% of the human population is homozygous for, predisposes for Crohn’s disease, and inflammatory bowel disease, and leprosy, a chronic infection with Mycobacterium leprae. FAMIN’s disease associations contrast markedly with genetic loss of ADA and PNP, which cause severe combined immunodeficiency. This lack of redundancy by these monofunctional enzymes corroborates our data that FAMIN is at the cusp of a distinct metabolon that controls immune function. This project will examine the mechanistic basis how FAMIN activity prevents autoinflammation and autoimmunity. A whole range of genetic in vitro and in vivo tools, high-end liquid chromatography mass-spectrometry techniques, and immunological methods and models are available to unravel how this biochemical mechanism prevents immunopathology.

“We discovered that GPR35 interacts with the α1-chain of the sodium/potassium ATPase (Na/K-ATPase) and thereby controls its pump and signalling function. GPR35T108M, which confers genetic risk for ulcerative colitis and primary sclerosing cholangitis, increases Na/K-ATPase’s pump
function by 25%, while deletion of Gpr35 decreases it by 30%. GPR35 also activates Na/K-ATPase dependent Src signalling, and Gpr35–/– mice are protected from developing tumours. Considering Na/K-ATPase’s quintessential role in maintaining the electrochemical gradient of a cell, we will address the structural basis of GPR35’s unique interaction with Na/K-ATPase. We will use molecular biological, biochemical, and structural (cryo-EM) methods to address this. We will elucidate the role of GPR35 in innate and adaptive immunity and its dependency on Na/K-ATPase and ion homeostasis in the context of inflammation.GPR35 is expressed in immune and intestinal epithelial cells. We will test how GPR35 modulates the interaction of macrophage, fibroblasts and epithelial cells and the consequent effects on the inflammatory tumour microenvironment which defines tumour growth and size.
We will use cell culture models including human pluripotent stem cells which will be differentiated into macrophages and intestinal organoids, molecular biology to develop cells expressing tagged GPR35 as no antibodies are available for this receptor. The project will also involve in vivo work (phenotyping of mice lacking GPR35 specifically in immune or intestinal epithelial cells), and some structural work on the receptor and its complex with the Na/K-ATPase.”

“”Single-stranded nucleic acids can be engineered to have biochemical activities, e.g. antisense oligos (ASOs), chemical antibodies (aptamers) and catalysts (ribozymes, DNAzymes), combining the advantageous properties of small molecules with the more sophisticated functions of complex biologics, e.g. monoclonals and enzymes. In principle, they offer a limitless variety of therapeutics, synthesised and stored as easily as a primer for PCR. Nonetheless, clinical applications have been hampered by the limitations of natural DNA or RNA backbones. Synthetic nucleic acid analogues, known as Xeno-nucleic acids (XNAs), with properties beyond DNA and RNA, offer a route to improved biostability and efficacy, as well as reduced immunogenicity.

Using SARS-CoV-2 as a model, we have previously shown that ‘programmable’ RNA-cleaving catalysts composed of XNA – “XNAzymes” – can be targeted to viral genomic RNA sequences with remarkable precision, with the potential to provide a novel modality for treatment of RNA viruses.

Almost 40 years since it was discovered, the Human Immunodeficiency Virus (HIV) still causes more than 0.5 million AIDS-related deaths every year, particularly in low-income countries. In collaboration with Nick Matheson’s lab, this project will therefore explore the potential for XNAzymes to prevent the initiation and spread of HIV infection. After determining potential target sites in the HIV genome, we will establish a ‘design–build–test–learn’ cycle to engineer and screen bespoke nucleic acid catalysts, and optimise delivery mechanisms. The Taylor and Matheson labs are based in the brand new Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), including the largest academic Containment Level 3 (CL3) facility in the UK. This project will therefore offer the opportunity to move from basic chemical biology right through to testing novel candidate nucleic acid therapeutics against ‘live’ virus.”

“The lab recently coordinated a large multi-centre study of whole genome sequencing in primary immune deficiency. This demonstrated that Bayesian analytic approaches to large cohorts of patients with primary immune deficiency can identify new disease-causing genes. This work is ongoing, funded by a £4million grant from the Wellcome Trust (https://www.intrepidproject.info). These projects have thrown up a number of candidate genes that are highly likely to drive previously undescribed monogenic diseases, and to provide insight into the functioning of the human immune stem. Six such diseases have been described in the past two or three years, but most genes on the list remain unexplored. The candidate would explore the functional and clinical impact of a given gene defect through in vitro laboratory studies, working directly with patient samples and also potentially mouse models. The project would have the potential not only to describe new monogenic diseases, but to explore the relationship between common and rare variants in driving the variable clinical presentation of these diseases”.

“The Smith Lab studies patients with immune-mediated disease to understand pathogenesis and impact treatment. We have recruited cohorts of unusually well-characterised patients with a range of diseases including lupus, vasculitis, inflammatory bowel disease, idiopathic pulmonary fibrosis and others. Samples have been subject to detailed “omics” analyses, and immune data correlate with clinical outcomes over years. This has led to discovery of new pathways that control long term outcome, and to prognostic tests which are entering the clinic through a spin-out PredictImmune. Most datasets we have acquired are yet to be analysed, and represent a rich resource for students interested in human disease, novel approaches to data analysis and immunology. The precise focus of the project can be tailored to suit the student given the range of datasets available. Close collaboration with the MRC Biostatistics Unit will provide added analytic expertise, equipping students with a valuable skillset”.

“Non-typhoidal Salmonella infections are estimated to affect over 95 million people world-wide each year, and invasive infections can be especially life-threatening in young children and the elderly. A crucial role for the gut microbiota has long been observed in resistance to enteric infections. We recently developed biological and bioinformatic tools that allowed the discovery of a gut bacteria species that induces host protection against Salmonella pathogenesis. We now propose to combine comparative genomics and metabolomics to identify key microbial genes, metabolic pathways and metabolites from these bacteria and test them for in vitro and in vivo efficacy against Salmonella and other enteric pathogens“.