Live and inactivated Salmonella enterica serovar Typhimurium stimulate similar but distinct transcriptome profiles in bovine macrophages and dendritic cells.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major cause of gastroenteritis in cattle and humans. Dendritic cells (DC) and macrophages (Mø) are major players in early immunity to Salmonella, and their response could influence the course of infection. Therefore, the global transcriptional response of bovine monocyte-derived DC and Mø to stimulation with live and inactivated S. Typhimurium was compared. Both cell types mount a major response 2 h post infection, with a core common response conserved across cell-type and stimuli. However, three of the most affected pathways; inflammatory response, regulation of transcription and regulation of programmed cell death, exhibited cell-type and stimuli-specific differences. The expression of a subset of genes associated with these pathways was investigated further. The inflammatory response was greater in Mø than DC, in the number of genes and the enhanced expression of common genes, e.g., interleukin (IL) 1B and IL6, while the opposite pattern was observed with interferon gamma. Furthermore, a large proportion of the investigated genes exhibited stimuli-specific differential expression, e.g., Mediterranean fever. Two-thirds of the investigated transcription factors were significantly differentially expressed in response to live and inactivated Salmonella. Therefore the transcriptional responses of bovine DC and Mø during early S. Typhimurium infection are similar but distinct, potentially due to the overall function of these cell-types. The differences in response of the host cell will influence down-stream events, thus impacting on the subsequent immune response generated during the course of the infection.

Exploring the role of the epigenome in multiple sclerosis: a window onto cell-specific transcriptional potential.

The field of epigenomics involves the study of chromatin, the three dimensional complex of DNA, protein and non-coding RNAs that determines the accessibility of DNA by the transcriptional machinery. The epigenome varies from cell to cell and reflects the effect of external stimuli on cell fate and cell state. Thanks to emerging platforms and analysis methods, the systematic characterization of chromatin conformation throughout the genome has begun and has yielded several reference epigenome maps for a growing number of cell types. Such maps are enabling insights into the correlation architecture of different epigenomic marks: a number of discrete chromatin states are found across different cell types. The combination of these reference maps and robust platforms for genome-wide data generation has introduced a new era in which studies of human disease are becoming feasible. Little is known about the role of the epigenome in MS, but it is likely that, as in other inflammatory disease, susceptibility factors and events along the course of the disease will alter the chromatin state of different cell types in patients with MS. Here, we review different strategies for the characterization of the epigenome and how these strategies could be used to implement new studies to explore how alterations of chromatin architecture establish a dysregulated transcriptional state in the context of MS.

A 17q12 allele is associated with altered NK cell subsets and function.

NK cells play an important role in innate immunity. A previous genome-wide association study demonstrated an association between a 17q12 allele (rs9916629(C)) and lower frequency of CD3(-)CD56(+) NK cells in peripheral blood. We performed an analysis that not only replicates the original result of the genome-wide association study (p = 0.036) but also defines the specific cell subpopulations and functions that are modulated by the rs9916629 polymorphism in a cohort of 96 healthy adult subjects using targeted multiparameter flow cytometric profiling of NK cell phenotypes and functions. We found that rs9916629(C) is associated with alterations in specific NK cell subsets, including lower frequency of predominantly cytotoxic CD56(dim) NK cells (p = 0.011), higher frequency of predominantly regulatory CD56(bright) NK cells (p = 0.019), and a higher proportion of NK cells expressing the inhibitory NKG2A receptor (p = 0.0002). Functionally, rs9916629(C) is associated with decreased secretion of macrophage inflammatory protein-1ß by NK cells in the context of Ab-dependent cell-mediated cytotoxicity (p = 0.039) and increased degranulation in response to MHC class I-deficient B cells (p = 0.017). Transcriptional profiling of NK cells suggests that rs9916629 influences the expression of transcription factors such as TBX21, which has a role in NK cell differentiation, offering a possible mechanism for the phenotypic and functional differences between the different alleles. The rs9916629(C) allele therefore has a validated effect on the proportion of NK cells in peripheral blood and skews NK cells toward a specific phenotypic and functional profile, potentially influencing the impact that these innate immune cells have on infection and autoimmunity.

The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors.

The tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Theileriosis. The parasite predominantly invades bovine macrophages (m phi) and induces host cell transformation by a mechanism that has not been fully elucidated. Infection is associated with loss of characteristic m phi functions and phenotypic markers, indicative of host cell de-differentiation. We have investigated the effect of T. annulata infection on the expression of the m phi differentiation marker c-maf. The up-regulation of c-maf mRNA levels observed during bovine monocyte differentiation to m phi was suppressed by T. annulata infection. Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived m phi. Treatment of T. annulata-infected cells with the theileriacidal drug buparvaquone induced up-regulation of c-maf and mafB, which correlated with altered expression of down-stream target genes, e.g. up-regulation of integrin B7 and down-regulation of IL12A. Furthermore, T. annulata infection is associated with the suppression of the transcription factors, Pu.1 and RUNX1, and colony stimulating factor 1 receptor (CSF1R) which are also involved in the regulation of monocyte/m phi differentiation. We believe these results provide the first direct evidence that T. annulata modulates the host m phi differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation. Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected m phi.