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A genome-wide association study of fetal response to type 2 porcine reproductive and respiratory syndrome virus challenge.

ABSTRACT: Control of porcine reproductive and respiratory syndrome (PRRS) is economically important for the swine industry worldwide. As current PRRS vaccines do not completely protect against heterologous challenge, alternative means of control, including enhanced genetic resilience, are needed. For reproductive PRRS, the genetic basis of fetal response to PRRS virus (PRRSV) infection is poorly understood. Genome-wide association studies (GWAS) were done here using data from 928 fetuses from pregnant gilts experimentally challenged with type 2 PRRSV. Fetuses were assessed for viral load in thymus (VLT), viral load in endometrium (VLE), fetal death (FD) and fetal viability (FV), and genotyped at a medium density. Collectively, 21 candidate genomic regions were found associated with these traits, seven of which overlap with previously reported QTLs for pig health and reproduction. A comparison with ongoing and related transcriptomic analyses of fetal response to PRRSV infection found differentially expressed genes within 18 candidate regions. Some of these genes have immune system functions, and have been reported to contribute to host response to PRRSV infection. The results provide new evidence about the genetic basis of fetal response to PRRSV challenge, and may ultimately lead to alternative control strategies to reduce the impact of reproductive PRRS.

SUBMITTER: Yang T

PROVIDER: S-EPMC4742883 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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A genome-wide association study of fetal response to type 2 porcine reproductive and respiratory syndrome virus challenge.

Yang Tianfu T Wilkinson James J Wang Zhiquan Z Ladinig Andrea A Harding John J Plastow Graham G

Scientific reports 20160205

Control of porcine reproductive and respiratory syndrome (PRRS) is economically important for the swine industry worldwide. As current PRRS vaccines do not completely protect against heterologous challenge, alternative means of control, including enhanced genetic resilience, are needed. For reproductive PRRS, the genetic basis of fetal response to PRRS virus (PRRSV) infection is poorly understood. Genome-wide association studies (GWAS) were done here using data from 928 fetuses from pregnant gil ...[more]

PMID: 26846722

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Project description:Introduction: Porcine reproductive and respiratory syndrome virus (PRRSV) causes respiratory disease in piglets and reproductive disease in sows. Piglet and fetal serum thyroid hormone (i.e., T3 and T4) levels decrease rapidly in response to Porcine reproductive and respiratory syndrome virus infection. However, the genetic control of T3 and T4 levels during infection is not completely understood. Our objective was to estimate genetic parameters and identify quantitative trait loci (QTL) for absolute T3 and/or T4 levels of piglets and fetuses challenged with Porcine reproductive and respiratory syndrome virus. Methods: Sera from 5-week-old pigs (N = 1792) at 11 days post inoculation (DPI) with Porcine reproductive and respiratory syndrome virus were assayed for T3 levels (piglet_T3). Sera from fetuses (N = 1,267) at 12 or 21 days post maternal inoculation (DPMI) with Porcine reproductive and respiratory syndrome virus of sows (N = 145) in late gestation were assayed for T3 (fetal_T3) and T4 (fetal_T4) levels. Animals were genotyped using 60 K Illumina or 650 K Affymetrix single nucleotide polymorphism (SNP) panels. Heritabilities, phenotypic correlations, and genetic correlations were estimated using ASREML; genome wide association studies were performed for each trait separately using Julia for Whole-genome Analysis Software (JWAS). Results: All three traits were low to moderately heritable (10%–16%). Phenotypic and genetic correlations of piglet_T3 levels with weight gain (0–42 DPI) were 0.26 ± 0.03 and 0.67 ± 0.14, respectively. Nine significant quantitative trait loci were identified for piglet_T3, on Sus scrofa chromosomes (SSC) 3, 4, 5, 6, 7, 14, 15, and 17, and collectively explaining 30% of the genetic variation (GV), with the largest quantitative trait loci identified on SSC5, explaining 15% of the genetic variation. Three significant quantitative trait loci were identified for fetal_T3 on SSC1 and SSC4, which collectively explained 10% of the genetic variation. Five significant quantitative trait loci were identified for fetal_T4 on SSC1, 6, 10, 13, and 15, which collectively explained 14% of the genetic variation. Several putative immune-related candidate genes were identified, including CD247, IRF8, and MAPK8. Discussion: Thyroid hormone levels following Porcine reproductive and respiratory syndrome virus infection were heritable and had positive genetic correlations with growth rate. Multiple quantitative trait loci with moderate effects were identified for T3 and T4 levels during challenge with Porcine reproductive and respiratory syndrome virus and candidate genes were identified, including several immune-related genes. These results advance our understanding of growth effects of both piglet and fetal response to Porcine reproductive and respiratory syndrome virus infection, revealing factors associated with genomic control of host resilience.

Project description:BackgroundMechanisms of fetal death following maternal PRRSV2 infection remain uncharacterized, although hypoxia from umbilical cord lesions and/or placental detachment due to apoptosis are hypothesized. We performed two experiments examining hypoxia and apoptosis in PRRSV-infected and non-infected, third-trimester fetuses to elucidate possible associations with fetal death. Fetuses were selected based on four phenotypic infection groups: fetuses from non-challenged control gilts (CTRL); low viral load fetuses (LVL; Exp 1) or uninfected fetuses (UNINF; Exp 2) from inoculated gilts; viable high viral load fetuses (HVL-VIA); and HVL meconium-stained fetuses (HVL-MEC).ResultsIn experiment 1, paraffin embedded fetal tissues collected 21 days post maternal infection (DPI) were examined for DNA fragmentation associated with apoptosis. Positively stained foci were larger and more numerous (P < 0.05) in heart, liver, and thymus of HVL-VIA and HVL-MEC compared to CTRL and LVL fetuses. In experiment 2, group differences in gene expression within the hypoxia (HIF1a, IDO1, VEGFa, LDHA, NOS2, NOX1) and apoptosis (CASP3, CASP7, CASP8, CASP9, RIPK1, RIPK3) pathways were assessed by RT-qPCR in fetal tissues collected at 12 DPI. High viral load fetuses showed differential expression relative to the CTRL and UNINF (P < 0.05 for all). Brain tissue from HVL-VIA and HVL-MEC fetuses presented increased expression of CASP7, CASP8, RIPK3, HIF1a and IDO1. Fetal heart showed increased expression of CASP8, HIF1a, IDO and NOX1 and a decrease in NOS2 expression in infected groups. CASP7, CASP9, RIPK1 and RIPK3 were only increased in the heart of HVL-VIA while VEGFa was only increased for HVL-MEC fetuses. Thymus from HVL-MEC had decreased expression of CASP9 and there was increased IDO1 in all infected fetuses.ConclusionsThere is strong evidence of apoptosis occurring in the heart, liver and thymus of highly viral load fetuses at 21 DPI. Furthermore, there was clear upregulation of apoptotic genes in the heart of high viral load infected fetuses and less prominent upregulation in the brain of PRRSV-infected fetuses, whereas thymus appears to be spared at 12 DPI. There was no strong evidence of hypoxia at 12 DPI in brain and thymus but some indication of hypoxia occurring in fetal heart.

Project description:Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection of pregnant pigs can result in congenital infection and ultimately fetal death. Little is known about immune responses to infection at the maternal-fetal interface and in the fetus itself, or the molecular events behind virus transmission and disease progression in the fetus. To investigate these processes, RNA-sequencing of two sites, uterine endothelium with adherent placental tissue and fetal thymus, was performed 21 days post-challenge on four groups of fetuses selected from a large PRRSV challenge experiment of pregnant gilts: control (CON), uninfected (UNINF), infected (INF), and meconium-stained (MEC) (n?=?12/group). Transcriptional analyses consisted of multiple contrasts between groups using two approaches: differential gene expression analysis and weighted gene co-expression network analysis (WGCNA). Biological functions, pathways, and regulators enriched for differentially expressed genes or module members were identified through functional annotation analyses. Expression data were validated by reverse transcription quantitative polymerase chain reaction (RTqPCR) carried out for 16 genes of interest.The immune response to infection in endometrium was mainly adaptive in nature, with the most upregulated genes functioning in either humoral or cell-mediated immunity. In contrast, the expression profile of infected fetal thymus revealed a predominantly innate immune response to infection, featuring the upregulation of genes regulated by type I interferon and pro-inflammatory cytokines. Fetal infection was associated with an increase in viral load coupled with a reduction in T cell signaling in the endometrium that could be due to PRRSV-controlled apoptosis of uninfected bystander cells. There was also evidence for a reduction in TWIST1 activity, a transcription factor involved in placental implantation and maturation, which could facilitate virus transmission or fetal pathology through dysregulation of placental function. Finally, results suggested that events within the fetus could also drive fetal pathology. Thymus samples of meconium-stained fetuses exhibited an increase in the expression of pro-inflammatory cytokine and granulocyte genes previously implicated in swine infectious disease pathology.This study identified major differences in the response to PRRSV infection in the uterine endometrium and fetus at the gene expression level, and provides insight into the molecular basis of virus transmission and disease progression.

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A genome-wide association study of fetal response to type 2 porcine reproductive and respiratory syndrome virus challenge.

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A genome-wide association study of fetal response to type 2 porcine reproductive and respiratory syndrome virus challenge.

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