Traits associated with innate and adaptive immunity in pigs: heritability and associations with performance under different health status conditions

There is a need for genetic markers or biomarkers that can predict resistance towards a wide range of infectious diseases, especially within a health environment typical of commercial farms. Such markers also need to be heritable under these conditions and ideally correlate with commercial performance traits. In this study, we estimated the heritabilities of a wide range of immune traits, as potential biomarkers, and measured their relationship with performance within both specific pathogen-free (SPF) and non-SPF environments. Immune traits were measured in 674 SPF pigs and 606 non-SPF pigs, which were subsets of the populations for which we had performance measurements (average daily gain), viz. 1549 SPF pigs and 1093 non-SPF pigs. Immune traits measured included total and differential white blood cell counts, peripheral blood mononuclear leucocyte (PBML) subsets (CD4+ cells, total CD8α+ cells, classical CD8αβ+ cells, CD11R1+ cells (CD8α+ and CD8α-), B cells, monocytes and CD16+ cells) and acute phase proteins (alpha-1 acid glycoprotein (AGP), haptoglobin, C-reactive protein (CRP) and transthyretin). Nearly all traits tested were heritable regardless of health status, although the heritability estimate for average daily gain was lower under non-SPF conditions. There were also negative genetic correlations between performance and the following immune traits: CD11R1+ cells, monocytes and the acute phase protein AGP. The strength of the association between performance and AGP was not affected by health status. However, negative genetic correlations were only apparent between performance and monocytes under SPF conditions and between performance and CD11R1+ cells under non-SPF conditions. Although we cannot infer causality in these relationships, these results suggest a role for using some immune traits, particularly CD11R1+ cells or AGP concentrations, as predictors of pig performance under the lower health status conditions associated with commercial farms

Increased Abundance of M cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases

Advanced tests for early and accurate diagnosis of Creutzfeldt-Jakob disease

Early and accurate diagnosis of Creutzfeldt-Jakob disease (CJD) is a necessary to distinguish this untreatable disease from treatable rapidly progressive dementias, and to prevent iatrogenic transmission. Currently, definitive diagnosis of CJD requires detection of the abnormally folded, CJD-specific form of protease-resistant prion protein (PrP(CJD)) in brain tissue obtained postmortem or via biopsy; therefore, diagnosis of sporadic CJD in clinical practice is often challenging. Supporting investigations, including MRI, EEG and conventional analyses of cerebrospinal fluid (CSF) biomarkers, are helpful in the diagnostic work-up, but do not allow definitive diagnosis. Recently, novel ultrasensitive seeding assays, based on the amplified detection of PrP(CJD), have improved the diagnostic process; for example, real-time quaking-induced conversion (RT-QuIC) is a sensitive method to detect prion-seeding activity in brain homogenate from humans with any subtype of sporadic CJD. RT-QuIC can also be used for in vivo diagnosis of CJD: its diagnostic sensitivity in detecting PrP(CJD) in CSF samples is 96%, and its specificity is 100%. Recently, we provided evidence that RT-QuIC of olfactory mucosa brushings is a 97% sensitive and 100% specific for sporadic CJD. These assays provide a basis for definitive antemortem diagnosis of prion diseases and, in doing so, improve prospects for reducing the risk of prion transmission. Moreover, they can be used to evaluate outcome measures in therapeutic trials for these as yet untreatable infections