Publications

Resistance to infection with enteric pathogens such as Salmonella and Campylobacter can be at many levels and include both non-immune and immune mechanisms. Immune resistance mechanisms can be specific, at the level of the adaptive immune response, or non-specific, at the level of the innate immune response. Whilst we can extrapolate to some degree in birds from what is known about immune responses to these pathogens in mammals, chickens are not "feathered mice", but have a different repertoire of genes, molecules, cells and organs involved in their immune response compared to mammals. Fundamental work on the chicken's immune response to enteric pathogens is therefore still required. Our studies focus particularly on the innate immune response, as responses of heterophils (the avian neutrophil equivalent) from commercial birds, and macrophages from inbred lines of chickens, correlate with resistance or susceptibility to Salmonella infection with a variety of Salmonella serovars and infection models. We work on two basic resistance mechanisms - resistance to colonization with Salmonella or Campylobacter, and resistance to systemic salmonellosis (or fowl typhoid). To map genes involved in resistance to colonization with Salmonella and Campylobacter, we are using a combination of expression quantitative trait loci (eQTLs) from microarray studies, allied with whole genome SNP arrays (WGA), a candidate gene approach and analysis of copy number variation across the genome. For resistance to systemic salmonellosis, we have refined the location ofa novel resistance locus on Chromosome 5, designated SAL1, using high density SNP panels, combined with advanced back-crossing of resistant and susceptible lines. Using a 6th generation backcross mapping population we have confirmed and refined the SAL1 locus to 8-00 kb of Chromosome 5. This region spans 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC-alpha serine/threonine protein kinase homologue, AKT1.

The susceptibility to multiple sclerosis (MS), a chronic neurological autoimmune disease that primarily targets CNS myelin, has long been associated with HLA class-II genes. Although several other HLA and non-HLA disease predisposing alleles have been identified, alleles of the HLA-DR15 haplotype (DRB1*1501, DRB5*0101, and DQB1*0602) remain the strongest susceptibility factor. Many studies have suggested that the HLA-DRB1*1501 allele determines MS-associated susceptibility. However, due to strong linkage disequilibrium within the HLA class II region, it has been difficult to unequivocally determine the relative roles of the DRB1*1501 and DQB1*0602 products. In this study we use HLA class-II transgenic mice to illuminate the relative contributions of the DRB1*1501 and DQB1*0602 alleles or their combination to susceptibility toward a new “humanized” MS-like disease induced by myelin-associated oligodendrocytic basic protein (MOBP). Although many immunological studies have focused overwhelmingly on the role of the HLA-DRB1*1501 product in MS, we show that HLA-DRB1*1501 transgenics are refractory to MOBP disease induction, whereas the HLA-DQB1*0602 transgenics are susceptible via T cells reactive against MOBP15–36 and MOBP55–77 encephalitogenic epitopes. Although both transgenics react against these epitopes, the MOBP15–36- and MOBP55–77-reactive T cells are of Th2-type in HLA-DRB1*1501 transgenics and are pathogenic Th1/Th17 cells in the HLA-DQB1*0602 transgenic mice. This new humanized model of MS further implicates autoimmunity against MOBP in MS pathogenesis, provides the first evidence of pathogenic HLA-DQ-associated anti-myelin autoimmunity, and is the first to offer a rationale for HLA-DQB1*0602 association with MS. These findings have important bearing on the candidacy of the DQB1*0602 allele as a genetic risk factor for MS.

Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type I IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection.