The pregnane X receptor drives sexually dimorphic hepatic changes in lipid and xenobiotic metabolism in response to gut microbiota in mice.

The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion using antibiotics in Pxr <sup>+/+</sup> vs Pxr <sup>-/-</sup> C57BL/6J littermate mice followed by hepatic transcriptomics revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis suggested that microbiota-PXR interaction controlled fatty acid and xenobiotic metabolism. We confirmed that antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in the liver from Pxr <sup>+/+</sup> but not Pxr <sup>-/-</sup> male mice. These findings identify PXR as a hepatic effector of microbiota-derived signals that regulate the host's sexually dimorphic lipid and xenobiotic metabolisms in the liver. Thus, our results reveal a potential new mechanism for unexpected drug-drug or food-drug interactions. Video abstract

Cellular and Molecular Mechanisms Underlying the Strong Neonatal IL-12 Response of Lamb Mesenteric Lymph Node Cells to R-848

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Group Space Allowance Has Little Effect on Sow Health, Productivity, or Welfare in a Free-Access Stall System

Free-access stalls allow sows to choose the protection of a stall or use of a shared group space. This study investigated the effect of group space width, 0.91 (SS), 2.13 (IS), and 3.05 (LS) m, on the health, production, behavior, and welfare of gestating sows. Nine replications of 21 (N = 189) gestating sows were used. At gestational d 35.4 ± 2.3, the pregnant sows were distributed into 3 pens of 7 sows, where they remained until 104.6 ± 3.5 d. Each treatment pen had 7 free-access stalls and a group space that together provided 1.93 (SS), 2.68 (IS), or 3.24 (LS) m2/sow. Baseline measurements were obtained before mixing. Back fat depth, BW, BCS, and lameness were measured monthly, and skin lesions were scored weekly. Blood was collected monthly for hematological, immunological, and cortisol analyses. Sow behavior was video recorded continuously during the initial 4 d of treatment and 24 h every other week thereafter. Behavior was analyzed for location, posture, pen investigation, social contact, and aggression. Skin response to the mitogen concanavalin A (Con A) was tested at mean gestational d 106. Litter characteristics including size and weight were collected at birth and weaning. The data were analyzed using a mixed model. Multiple comparisons were adjusted with the Tukey-Kramer and Bejamini-Hochberg methods. Group space allowance had no effect on any measure of sow health, physiology, or production (P ≥ 0.10). Sows in the SS, IS, and LS pens spent 77.88% ± 3.88%, 66.02% ± 3.87%, and 63.64% ± 3.91%, respectively, of their time in the free-access stalls (P = 0.12). However, SS sows used the group space less than IS and LS sows (P = 0.01). Overall, pen investigatory behavior was not affected by group space allowance (P = 0.91). Sows in the LS pens spent more time in a social group than SS sows (P = 0.02), whereas sows in IS pens were intermediate to, but not different from, the other treatments (P ≥ 0.10). The size of the social groups was also affected by the group space allowance (P = 0.03), with SS sows forming smaller groups than LS sows; again, IS sows were intermediate to, but not different from, the other treatments. Although the group space allowance had no measurable impact on the health, physiology, or productivity of the sows, the lower group space use and social contact of the SS sows reduced the behavioral diversity benefits of group housing and may indicate an avoidance of social stressors or a lack of physical comfort in the smallest pens

Precision engineering for PRRSV resistance in pigs: Macrophages from genome edited pigs lacking CD163 SRCR5 domain are fully resistant to both PRRSV genotypes while maintaining biological function

Porcine Reproductive and Respiratory Syndrome (PRRS) is a panzootic infectious disease of pigs, causing major economic losses to the world-wide pig industry. PRRS manifests differently in pigs of all ages but primarily causes late-term abortions and stillbirths in sows and respiratory disease in piglets. The causative agent of the disease is the positive-strand RNA PRRS virus (PRRSV). PRRSV has a narrow host cell tropism, limited to cells of the monocyte/macrophage lineage. CD163 has been described as a fusion receptor for PRRSV, whereby the scavenger receptor cysteine-rich domain 5 (SRCR5) region was shown to be an interaction site for the virus in vitro. CD163 is expressed at high levels on the surface of macrophages, particularly in the respiratory system. Here we describe the application of CRISPR/Cas9 to pig zygotes, resulting in the generation of pigs with a deletion of Exon 7 of the CD163 gene, encoding SRCR5. Deletion of SRCR5 showed no adverse effects in pigs maintained under standard husbandry conditions with normal growth rates and complete blood counts observed. Pulmonary alveolar macrophages (PAMs) and peripheral blood monocytes (PBMCs) were isolated from the animals and assessed in vitro. Both PAMs and macrophages obtained from PBMCs by CSF1 stimulation (PMMs) show the characteristic differentiation and cell surface marker expression of macrophages of the respective origin. Expression and correct folding of the SRCR5 deletion CD163 on the surface of macrophages and biological activity of the protein as hemoglobin-haptoglobin scavenger was confirmed. Challenge of both PAMs and PMMs with PRRSV genotype 1, subtypes 1, 2, and 3 and PMMs with PRRSV genotype 2 showed complete resistance to viral infections assessed by replication. Confocal microscopy revealed the absence of replication structures in the SRCR5 CD163 deletion macrophages, indicating an inhibition of infection prior to gene expression, i.e. at entry/fusion or unpacking stages

Transcription analysis on response of swine lung to H1N1 swine influenza virus

<p>Abstract</p> <p>Background</p> <p>As a mild, highly contagious, respiratory disease, swine influenza always damages the innate immune systems, and increases susceptibility to secondary infections which results in considerable morbidity and mortality in pigs. Nevertheless, the systematical host response of pigs to swine influenza virus infection remains largely unknown. To explore it, a time-course gene expression profiling was performed for comprehensive analysis of the global host response induced by H1N1 swine influenza virus in pigs.</p> <p>Results</p> <p>At the early stage of H1N1 swine virus infection, pigs were suffering mild respiratory symptoms and pathological changes. A total of 268 porcine genes showing differential expression (DE) after inoculation were identified to compare with the controls on day 3 post infection (PID) (Fold change ≥ 2, p < 0.05). The DE genes were involved in many vital functional classes, mainly including signal transduction, immune response, inflammatory response, cell adhesion and cell-cell signalling. Noticeably, the genes associated with immune and inflammatory response showed highly overexpressed. Through the pathway analysis, the significant pathways mainly concerned with Cell adhesion molecules, Cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway and MAPK signaling pathway, suggesting that the host took different strategies to activate these pathways so as to prevent virus infections at the early stage. However, on PID 7, the predominant function classes of DE genes included signal transduction, metabolism, transcription, development and transport. Furthermore, the most significant pathways switched to PPAR signaling pathway and complement and coagulation cascades, showing that the host might start to repair excessive tissue damage by anti-inflammatory functions. These results on PID 7 demonstrated beneficial turnover for host to prevent excessive inflammatory damage and recover the normal state by activating these clusters of genes.</p> <p>Conclusions</p> <p>This study shows how the target organ responds to H1N1 swine influenza virus infection in pigs. The observed gene expression profile could help to screen the potential host agents for reducing the prevalence of swine influenza virus and further understand the molecular pathogenesis associated with H1N1 infection in pigs.</p

Immunosuppression during Acute Infection with Foot-and-Mouth Disease Virus in Swine Is Mediated by IL-10

Foot-and-mouth disease virus (FMDV) is one of the most contagious animal viruses, causing a devastating disease in cloven-hoofed animals with enormous economic consequences. Identification of the different parameters involved in the immune response elicited against FMDV remains unclear, and it is fundamental the understanding of such parameters before effective control measures can be put in place. In the present study, we show that interleukin-10 (IL-10) production by dendritic cells (DCs) is drastically increased during acute infection with FMDV in swine. In vitro blockade of IL-10 with a neutralizing antibody against porcine IL-10 restores T cell activation by DCs. Additionally, we describe that FMDV infects DC precursors and interferes with DC maturation and antigen presentation capacity. Thus, we propose a new mechanism of virus immunity in which a non-persistent virus, FMDV, induces immunosuppression by an increment in the production of IL-10, which in turn, reduces T cell function. This reduction of T cell activity may result in a more potent induction of neutralizing antibody responses, clearing the viral infection