Research in Veterinary Medicine

Infection and immunity

Since 2001, the Infection and Immunity group has published in excess of 350 peer-reviewed papers and reviews, including papers in Science, Nature, Nature Genetics, PNAS and PLoS-Biology. The research has been mainly directed at mechanisms used by bacteria and viruses to infect and persist in hosts, and immunity to these pathogens. The Cambridge Infectious Diseases Consortium (CIDC), established in 2005, has focused on multidisciplinary studies of infection and disease-dynamics. This cross-cutting approach involves extensive collaboration with other Departments in the University, other UK University departments, most major animal health Institutes in the UK, as well as the Sanger Institute, and importantly with major international groups overseas.

http://www.infectiousdisease.cam.ac.uk

Themes

Bacterial pathogenesis

Notable advances have been made in understanding in vivo host-pathogen interactions at the single cell level, providing a substantial refinement of previous approaches (Mastroeni, Maskell, Grant). This research has pioneered the integration of mathematical models with observational data of individual bacteria within host cells and has greatly benefited from collaboration with members of CIDC.

An ex vivo air-interface respiratory tract organ culture has been developed as a model of bacterial adhesion (Maskell, Tucker). This model allows rapid analysis of host-bacterial interactions immediately following inoculation of respiratory pathogens. Tucker has also investigated inherited differences in host susceptibility to Haemophilus parasuis infection.

Functional genomics studies are another key interest. Whole-genome screens for genes required for colonization and virulence have been performed in Salmonella enterica and Campylobacter jejuni in their farm animal hosts, and completely novel genome screening methodologies have been invented and patented e.g. transposon mediated differential hybridization (Maskell). This work has dove-tailed with Maskell's central role in driving the genome sequencing of several pathogens of interest to veterinary and human medicine at the Sanger Institute.

Immunity to infection

Immunity and vaccine development are a major focus (Mastroeni, Bryant, Maskell, Grant). Mastroeni has studied how different classes of antibody enhance intracellular pathways of bacterial killing by host cells and how B-cells interact with T-cells in vivo to promote the development of protective Th1 cellular immunity to infection. Mastroeni has also investigated new ways to optimise immune responses induced by the new generations of bacterial vaccines against S. enterica. Research in collaboraation with Professor Anne Cooke (Department of Pathology) has studied the interaction between bacterial infections and autoimmune diseases identifying immunological mechanisms induced by microorganisms that protect against autoimmune diabetes. Mastronei's involvement with the Sanger Instutute has identified novel genes that are involved in host immunity to bacterial infection and has studied aspects of pathogenesis, transmission and immunity in Clostridium difficile infections.

Lipopolysaccharide (LPS)-induced activation of Toll-like receptor 4 (TLR4) has been identified as a key factor in the host protective immune response to Salmonella enterica (Bryant, Maskell). Different signaling pathways activated by TLR4 to induce innate and adaptive immune responses to Salmonella infection have been elucidated. Infection with S. enterica regulates expression of other TLRs, which are important in bacterial pathogenesis. The comparative biology of ligand interactions at the TLR4/MD2 protein complex has been elucidated using human, mouse, cat and horse receptor constructs.

The microbial immunology group led by Lachmann has studied the 'Streptococcal Inhibitor of Complement' (SIC) in M1 Group A Streptococci. They have discovered that SIC is a multi-functional inhibitor of the innate immune response in the throat and upper airways and have mapped the relevant binding sites in order to identify SIC-antagonists as anti-streptococcal agents.

Kaufman has continued exploring the consequences of the "minimal essential MHC" of the chicken, showing that only one class I and class II molecule is expressed in each haplotype, and that the properties of the single dominantly-expressed molecule can explain the strong genetic associations of the chicken MHC with resistance to certain infectious pathogens as well as response to vaccines. Original studies on avian cytokines and chemokines in immunity to Salmonella enterica and the first identification of the avian dendritic cell in the chicken have been published by Professor Ian McConnell).

Virology

Blacklaws and McConnell have further characterized the key role of dendritic cells in the presentation of viral antigens by a lentivirus (Maedi-Visna virus, MVV) defining the role of T-cell epitopes in immunity to viral infection.

Heeney has studied host immune responses to RNA viruses, using this information to design novel vaccines for diseases caused by viruses for which vaccine development is notoriously difficult. Recent work has included; establishment of large international consortia to evaluate vaccine-induced immune responses; development of sensitive, quantifiable virological and immunological systems for the assessment of vaccines; the evolution of immune mechanisms of disease protection in naturally-infected, disease-resistant species.

Work on antiviral therapies, led by Dr Hugh Field, has demonstrated the efficacy of herpes antivirals (helicase-primase inhibitors) in infection models. Mechanisms of action have been characterized and studies on the occurrence of drug resistance mutations are informing clinical development. Studies of feline herpesvirus thymidine kinase provide a basis for future therapy using both existing and novel nucleosides.

Regulatory sequences of RNA viruses (influenza virus and FMD) have been studied by Tiley. The interaction of influenza virus polymerase with viral genome RNA has provided an understanding of how virus gene expression is regulated and indicated its potential as an antiviral target. The development of inhibitory RNA strategies against influenza virus led to the production of transgenic chickens with increased resistance to influenza.

Mumford has led the global surveillance and vaccine strain selection programme for equine influenza, focussing on the divergence of equine H3N8 lineages. The dynamics of variation of equine and porcine influenza viruses and their within-host infection dynamics have been explored by Mumford and Wood.

Disease dynamics

Professor James Wood leads a multi-disciplinary research group on infectious disease dynamics. Much of the ongoing activity is the legacy of the Cambridge Infectious Diseases Consortium (CIDC), part of the UK-wide Defra-funded Veterinary Training and Research Initiative (2005-2009), comprising mathematical modellers and statisticians who collaborate with microbiologists and clinicians in the study of infection dynamics. Wildlife infection dynamics of emergent infections such as tuberculosis are a focus of Pearce. Parasitology studies (Lloyd) have examined the biology and epidemiology of protozoa and helminths of game birds, rabbits and horses.

Prion studies

A significant programme of research in the area of prion diseases has been developed. Its focus is the molecular pathogenesis of prion diseases emphasising the expression of PrPC and PrPSc in lymphoid tissue (LRS); the structural biology of PrP; and the development of diagnostic tests for prion diseases. Significant achievements include: identification of roles for pro- and anti-inflammatory cytokines in the initiation and regulation of prion pathology (Bujdoso); detection of high levels of prion infectivity in animals with sub-clinical disease following low-dose prion inoculation (Thackray, Bujdoso); increased susceptibility to acute HSV-1 infection of mice expressing normal or increased levels of PrPC (Bujdoso). Recombinant PrP proteins have been used to generate anti-PrP monoclonal antibodies Barnard, McConnell andThackray). These have been used to show that the region between helix-1 and residue 171 of PrPC on ovine PBMCs displays considerable genotypic heterogeneity (Thackray). Using sheep of different genotypes McConnell has shown that PrP genotype affects PrPSc distribution on the follicular dendritic cell (FDC) network, but with no functional consequences for immune cell profiles. Our anti-PrP monoclonal antibodies have been used to develop novel diagnostic tests for prion diseases (Barnard, McConnell Thackray) leading to International patent applications for immuno-based prion protein detection assays.