Project Title: Role of innate lymphoid cells in the pathogenesis of hepatocellular carcinoma
Lay Summary: Innate lymphoid cells represent a novel population of immune cells that are important in the control of infections, but also contribute to allergic and autoimmune disease. However their role in the potential control of malignant disease has not been well studied. We will investigate whether innate lymphoid cells are present in lesional hepatocellular carcinoma (liver cancer) tissue and will define the subtype of innate lymphoid cells present. We will investigate the cell surface molecules expressed by the innate lymphoid cells, including molecules which may be important in how the innate lymphoid cells respond to the tumour cells. These experiments will allow us to define, for the first time, whether innate lymphoid cells have a role in the control of liver cancer cells and to investigate possible opportunities for therapeutic intervention.
Project Title: The impact of IFITM3 variants on HCV and HIV virus co-infection
Lay Summary: Lay Summary * 170 million people are infected with hepatitis C virus (HCV), which may lead to chronic liver disease, liver cirrhosis and hepatocellular carcinoma. Because of shared routes of transmission, HCV co-infection is recognized as a major cause of morbidity and mortality among human immunodeficiency virus type 1 (HIV- 1) infected persons. Effective drugs to control these infectious agents are limited and treatment is made even more challenging by the development of drug-resistant pathogens. Importantly, co-infection with one or more of these pathogens limits the efficacy of available drugs. The epidemiological and clinical features of co-infected subjects is well documented, however, there is a paucity of basic scientific studies addressing the molecular interaction(s) between these pathogens. Interferon inducible transmembrane protein-3 gene IFITM3 is known to restricting enveloped virus such as Influenza, HCV and HIV. It was recently shown that a SNP variant, the CC variant is greatly increased in frequency in severe acute influenza patients. We propose that host genetic variation such as IFITM3 may plays a key role in co-infection associated morbidity.
Project Title: Frequency and activity of myeloid derived suppressor cells in hepatocellular carcinoma
Lay Summary: Myeloid Derived Suppressor Cells (MDSC) have been shown to be able to suppress antigen specific immune responses. Several papers have demonstrated the ability of tumour cells to harness MDSC to hamper tumour specific immune responses. However, their role in Hepatocellular Carcinoma remains unclear. Furthermore, it is not clear whether their cross talk with innate immune cells can be harnessed to modify their suppressing properties. We will investigate whether MDSC are present in lesional hepatocellular carcinoma (liver cancer) tissue and will define their subtype and functional activity. These experiments will allow us to define, for the first time, whether MDSC have a role in the control of liver cancer cells and to investigate possible opportunities for therapeutic intervention.
Project Title: Innate immune responses in hepatitis B mediated liver disease
Lay Summary: Immune responses in the liver are thought to be a key driver of Hepatitis B mediated cirrhosis and development of Hep B associated hepatocellular carcinoma (HCC). Very little is still known of basic molecular parameters of the immune response to Hep B in human liver tissue. Increased accessibility to human explant samples and improved molecular techniques capable of interrogating pathways in single cells or small numbers of liver cell subsets can now shed light on pathways that may drive disease progression in chronic Hep B infection. In this work we will define the repertoire of innate immune receptors expressed in subsets of liver cells such as hepatocytes, liver stem cells and stromal cells in hep B cirrhosis and define their signaling response to nucleic acid ligands. We will compare the responses observed with cells derived from patients with slow and rapidly progressive disease, HCC, and non Hep B related liver disease. Similar assays will be performed to phenotype panels of HCCs. The data derived will shed light on defects in innate immunity in Hep B infection that may contribute to disease progression and act as platform to inform molecular pathogenesis studies examining the interaction of Hep B viral genes with innate immune signaling paths shown to relevant in human disease in vivo. The work will also act as platform to fund systems level studies and drug screens to optimise therapeutic regimens for HCC.
Project Title: Cytosolic DNA sensing in the liver during HBV infection
Lay Summary: Hepatitis B is an infectious illness of the liver caused by the hepatitis B virus. Acute infection causes liver inflammation, vomiting, jaundice, and, rarely, death. Chronic hepatitis B virus infection may eventually cause cirrhosis and liver cancer - a disease with poor response to all but a few current therapies. Hepatitis B virus is a hepadnavirus - hepa from hepatotropic (attracted to the liver) and dna because it has a DNA genome. Replication takes place in the liver.
Much remains to be learned about the immune response to HBV in the liver. We know that cells have specialized proteins called pattern-recognition receptors that detect viruses, typically very shortly after the infection. One such receptor is a protein called cGAS that detects viral DNA. Whether this "antenna" senses HBV in the liver is unknown.
In an exciting collaboration between the Chinese Academy of Medical Science and the University of Oxford, we propose to identify whether a link exists between the presence of the cGAS receptor and the severity of HBV infection. If this is indeed the case, new predictive tools could be developed based on our work and in the long-term perhaps novel treatments.
Project Title: Human Monoclonal Antibodies to H7N9 Influenza
Lay Summary: A new Pandemic Influenza Virus (H7N9) has evolved in birds in China and has acquired the ability to infect humans to cause a severe pneumonia resulting in death in approximately 30% of cases. At the moment infections in humans are relatively rare and spread between humans unusual. About one in three of the H7N9 viruses isolated are resistant to Tamiflu, so there would be no specific treatment available. We are developing human antibodies, isolated from patients convalescing from H7N9 infections, which could be used as a specific therapy. This type of treatment could be considered as an “immune transfusion” as the proteins used for treatment are natural products of the human immune system. We have already isolated a set of six candidate antibodies for development. We will use the funding to scale up production to derive detailed structural information on how the antibodies bind to the H7 viral spike protein, and start testing them for protection in model systems. These will be required in preparation for phase one clinical trials.
Project Title: Understanding the molecular basis of Type 1 Congenital Dyserythropoietic Anaemia
Lay Summary: Red blood cells are highly specialised cells that transport oxygen around the body. Childhood anaemia results from the failure to produce adequate numbers of red blood cells in the bone marrow. Approximately ~1 per 100,000 infants inherit a condition, called congenital dyserythropietic anaemia (CDA), which severely impairs their ability to produce red blood cells. The disease severity is variable with the worst cases being fatal during pregnancy or at birth. Other infants require blood transfusions at birth, which in some may be the start of lifelong dependency on blood transfusions. This is particularly onerous for the patients as the transfusions lead to iron overload, a life-threatening complication treated by daily injections to remove excess iron. In collaboration with the diagnostic service at the John Radcliffe Hospital we have established a clinic to diagnose rare forms of anaemia, in which we study several new cases every month. These cases are sent to us from many locations throughout the world. Our diagnostic strategy involves sequencing patients’ DNA to look for mutations in 52 genes known to be associated with inherited anaemias. While a targeted panel approach provides a molecular diagnosis in ~40% of cases, the majority of cases remain undiagnosed. In cases that are genuinely due to monogenic causes, this can result from mutations occurring in genes that are not included in the panel; these may be novel genes that are not known to be associated with anaemia, mutations in non-coding regions or disorders arising from copy number variation. Such cases can be analysed by whole genome sequencing, which provides a solution to all of the above limitations from targeted panels. The aims of this project are therefore to identify new genes and mutations underlying anaemia to expand the diagnostic range of our screening strategy and ultimately to better understand disease pathogenesis and improve treatment of these disorders. Our laboratory’s work on CDA-I has shown that 85% of patients have inherited mutations in one or the other of two genes (CDAN1 or C15ORF41), required when cells replicate their DNA. The functions of these genes are the subject of current investigation and this would be greatly facilitated by the identification of currently unknown partners of these genes. Identifying which gene(s), when mutated, are responsible for the remaining 15% of the CDA-I cases would provide valuable information about interacting partners or pathways that involve CDAN1 and C15ORF41 and cause CDA-I.