Showing papers by "John C. S. Harding published in 2019"
TL;DR: Daily variation in FI or duration at the feeder can be used as heritable measures of resilience and should be viewed as overall indicators of general resilience to a variety of stressors.
Abstract: The objective of this study was to extract novel phenotypes related to disease resilience using daily feed intake data from growing pigs under a multifactorial natural disease challenge that was designed to mimic a commercial environment with high disease pressure to maximize expression of resilience. Data used were the first 1,341 crossbred wean-to-finish pigs from a research facility in Quebec, Canada. The natural challenge was established under careful veterinary oversight by seeding the facility with diseased pigs from local health-challenged farms, targeting various viral and bacterial diseases, and maintaining disease pressure by entering batches of 60-75 pigs in a continuous flow system. Feed intake (FI) is sensitive to disease, as pigs tend to eat less when they become ill. Four phenotypes were extracted from the individual daily FI data during finishing as novel measures of resilience. The first two were daily variability in FI or FI duration, quantified by the root mean square error (RMSE) from the within individual regressions of FI or duration at the feeder (DUR) on age (RMSEFI and RMSEDUR). The other two were the proportion of off-feed days, classified based on negative residuals from a 5% quantile regression (QR) of daily feed intake or duration data on age across all pigs (QRFI and QRDUR). Mortality and treatment rate had a heritability of 0.13 (±0.05) and 0.29 (±0.07), respectively. Heritability estimates for RMSEFI, RMSEDUR, QRFI, and QRDUR were 0.21 (±0.07) 0.26 (±0.07), 0.15 (±0.06), and 0.23 (±0.07), respectively. Genetic correlations of RMSE and QR measures with mortality and treatment rate ranged from 0.37 to 0.85, with QR measures having stronger correlations with both. Estimates of genetic correlations of RMSE measures with production traits were typically low, but often favorable (e.g., -0.31 between RMSEFI and finishing ADG). Although disease resilience was our target, fluctuations in FI and duration can be caused by many factors other than disease and should be viewed as overall indicators of general resilience to a variety of stressors. In conclusion, daily variation in FI or duration at the feeder can be used as heritable measures of resilience.
79 citations
TL;DR: It is demonstrated that the PD-1 inhibitor, nivolumab, led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL)(NCT02631746), and a previously unappreciated origin of these malignant cells was revealed, and a novel connection between ATLL cells and tumor-resident Tregs was identified.
74 citations
TL;DR: The random forest model identified that 'viral load in fetal thymus' and duration of infection ('DPI') as the most important factors predicting fetal resilience and resistance and IUGR fetuses had lower viral load and were less frequently compromised or dead compared to non-IUGR and average cohorts.
20 citations
TL;DR: The critical role of HBZ is shown in driving ATL-associated bone loss through RANKL and denosumab is identified as a potential treatment to prevent bone complications in ATL patients.
Abstract: Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models. Humanized mice infected with HTLV-1 developed lymphoproliferative disease and continuous, progressive osteolytic bone lesions. HTLV-1 lacking HBZ displayed only modest delays to lymphoproliferative disease but significantly decreased disease-associated bone loss compared with HTLV-1-infected mice. Gene expression array of acute ATL patient samples demonstrated increased expression of RANKL, a critical regulator of osteoclasts. We found that HBZ regulated RANKL in a c-Fos-dependent manner. Treatment of HTLV-1-infected humanized mice with denosumab, a monoclonal antibody against human RANKL, alleviated bone loss. Using patient-derived xenografts from primary human ATL cells to induce lymphoproliferative disease, we also observed profound tumor-induced bone destruction and increased c-Fos and RANKL gene expression. Together, these data show the critical role of HBZ in driving ATL-associated bone loss through RANKL and identify denosumab as a potential treatment to prevent bone complications in ATL patients.
13 citations
TL;DR: Trophoblast cells are susceptible to PRRSV-2 infection and release live virions capable of inducing cytopathic effects in naïve cells, which suggests a possible mechanism by which PRRSv-2 can breach the MFI resulting in fetal infection and death.
9 citations
TL;DR: Network descriptive measures, as well as the results of the hypotheses testing indicate little significance in the roles of animal movement, animal transportation companies, and semen suppliers during the initial phase of the 2014 Canadian PED outbreak.
7 citations
TL;DR: This research demonstrates for the first time that the niche mucin environment produced by two infectious spirochete spp.
Abstract: This research demonstrates for the first time that the niche mucin environment produced by two infectious spirochete spp. is supported by a decrease in the electrogenic anionic secretory response t...
6 citations
TL;DR: The median times to elimination were relatively long, which could be due to how it was measured, decisions made at the level of individual herds or delays related to reporting PEDV elimination, and the availability of resources to manage an emerging production-limiting disease.
Abstract: Porcine epidemic diarrhea virus (PEDV) emerged into Canada in January of 2014. The virus was considered to be of high importance and the number of new cases were tracked using different mechanisms by stakeholders such as veterinary services from the provincial government and the swine industry. In addition to the initial date of infection, veterinary organizations in the swine industry maintained a disease control program (DCP) database that contained the date of declaration of freedom from PEDV in individual herds. Such data allowed for the determination of the duration of PEDV infection in individual herds based on herd type, year and season of diagnosis. Therefore, the objective of this study was to determine time to PEDV elimination in Ontario swine herds infected between 2014 and 2017, on the basis of records from the DCP database; and to identify factors associated with the likelihood of elimination. Duration of time to eliminate PEDV was estimated using Kaplan-Meier survival curves. The final Cox's proportional hazard model included herd type, season and year of diagnosis. The hazard of PEDV elimination for premises that were farrow-to-wean was 3.36 times larger (P-value: 0.044, 95% CI: 1.03, 10.93) than for farrow-to-feeder herds. Herds diagnosed in the summer and fall had hazard ratios of 1.40 (P-value: 0.044, 95% CI: 1.03, 10.93) and 7.32 (P-value: <0.001, 95% CI: 3.12, 17.18), respectively compared to herds diagnosed in the winter months. The hazard ratio for herds diagnosed in 2015 was 0.54 (P-value: 0.015, 95% CI: 0.33, 0.89) compared to herds diagnosed in 2014. Factors associated with time to elimination are likely reflective of the complexity of infection control practices applied in herds with different demographics and population structures, seasonal variability in the pathogen transmissibility, and the availability of resources to manage an emerging production-limiting disease. The median times to elimination were relatively long, which could be due to how it was measured, decisions made at the level of individual herds or delays related to reporting PEDV elimination. Design of control measures for production-limiting diseases at the regional level should take these factors into consideration.
5 citations
TL;DR: The results of this study push the date of first appearance of B. hampsonii in pigs in western Canada back to 2002, which is up to 7 years before the new species were first identified in fresh samples.
Abstract: Mucohaemorrhagic diarrhea associated with Brachyspira hampsonii infection has emerged as a production-limiting disease in western Canada. This pathogen was first described in North America in 2010, and reports of its detection occurred concurrently in western Canada and the United States. Since that time, Brachyspira hampsonii has been detected in Europe, both in pigs and in waterfowl. The origin of B. hampsonii and the timing and reasons for its emergence are unknown. We conducted a retrospective study of historic, archived cases of porcine colitis to determine when B. hampsonii was first evident in western Canada. A total of 206 samples from 114 cases submitted from 57 different farms or productions systems in 1984 and 1999-2009 were screened using real-time PCR assays targeting B. hampsonii genomovars I and II, and Brachyspira hyodysenteriae (the traditional agent of swine dysentery). In most cases, positive real-time PCR results were confirmed by amplification and sequencing of additional gene targets. A total of 9, 7 and 5 samples tested positive for B. hampsonii (I), B. hampsonii (II) or B. hyodysenteriae respectively. The results of this study push the date of first appearance of B. hampsonii in pigs in western Canada back to 2002 (B. hampsonii (I)) and 2006 (B. hampsonii (II)), which is up to 7 years before the new species were first identified in fresh samples.
3 citations
Journal Article•
TL;DR: Allegedly avirulent Brachyspira species most closely related to B murdochii can be associated with subclinical colitis and may be a concern for grow-finish pigs.
Abstract: Objective: Microbiological and virulence characterization of 2 moderately hemolytic Brachyspira strains. Materials and methods: Clinical isolates were obtained from diarrheic (3603-F2) and healthy (G79) pigs. Phenotypic characterization included assessment of hemolytic activity on blood agar and biochemical profiling. Genotyping was performed by sequencing the nicotinamide adenine dinucleotide oxidase (nox) gene, whole genome sequencing, and comparison to relevant Brachyspira. Pig inoculation included 4 treatment groups in 2 challenge experiments: negative control (sterile broth media; n = 12), positive control (Brachyspira hampsonii genomovar 2 strain 30446; n = 18), and 3603-F2 (n = 12) or G79 (n = 12). Fecal scoring and rectal swabbing for culture were performed daily. Animals were euthanized following onset of mucohemorrhagic diarrhea or between 21 and 28 days post inoculation (dpi). Gross and microscopic pathology were assessed. Terminal colon samples were used to characterize post-infection mucosal ion secretion. Results: Both strains were moderately hemolytic. Whole genome and nox sequencing identified 3603-F2 as Brachyspira murdochii and G79 as a novel strain. Both challenge trials revealed intestinal colonization, but no mucohemorrhagic diarrhea. Sporadic watery diarrhea was induced by 3603-F2 associated with a pattern of microscopic lesions similar to pigs with swine dysentery (positive controls). No diarrhea was observed in G79 inoculated pigs, but microscopic lesions were more severe than in controls. Both strains induced greater colonic anion secretory potential than negative controls 21 dpi. Implications: Allegedly avirulent Brachyspira species most closely related to B murdochii can be associated with subclinical colitis and may be a concern for grow-finish pigs.
1 citations
13 Aug 2019
TL;DR: Investigation of the levels of natural antibodies in blood from young healthy pigs as potential predictors of disease resilience suggested NAb and total IgG levels in blood were genetically correlated with their subsequent resilience after a polymicrobial challenge.
Abstract: In typical pig nucleus breeding programs, it is difficult to select pigs for disease resilience because the breeding animals are raised under high-health conditions. Thus, indicator traits that can be measured on young healthy pigs and that are genetically correlated with disease resilience in commercial environments are needed in order to be able select for disease resilience.
The objective of this study was to investigate the levels of natural antibodies (NAb) in blood from young healthy pigs as potential predictors of disease resilience. NAb and total IgG levels in blood were genetically correlated with their subsequent resilience after a polymicrobial challenge. Although further research is needed, these results suggest that NAb and IgG levels in blood measured on young healthy pigs can be used as indicator traits to select for improved disease resilience in pigs.
TL;DR: A sandwich ELISA using an anti-bovine CD163 antibody, LND68A, in conjunction with the porcine specific 2A10/11 antibody demonstrated that CD163 shedding from porcines alveolar macrophages increased following in vitro exposure to lipopolysaccharide or PRRSV-2 strain NVSL 97-7895.
TL;DR: The identified Quantitative Trait Loci have the potential to be used to select for improved immune response and provide new information on the genetic basis of response to infectious diseases in sows.
Abstract:
The objective of this study was to perform genome-wide association studies (GWAS) to identify Quantitative Trait Loci (QTL) associated with antibody response to infectious diseases in commercial sows. A total of 2,848 Large White x Landrace replacement gilts were sourced from 17 high-health multipliers (7 breeding companies; BC) and introduced to 23 commercial farms with a history of common pig diseases, following the standard acclimation procedures with an average of 53 animals per entry group (CG). Serum was used to quantify antibody response to swine influenza virus (SIV), Mycoplasma hyopneumoniae (MH), porcine circovirus type-2 (PCV2), and 8 serotypes of Actinobacillus pleuropneumoniae (APP1-3, 5, 7, 10, 12, and 13) at entry (S/PEntry), following acclimation (S/PAcclimation), and during parities 1 (S/PParity1) and 2 (S/PParity2). All animals were genotyped for 38,191 SNPs. GWAS was performed using BayesB (pi=0.99), with the fixed effect of CG and the random effects of SNPs in the model. For APP, QTL were only identified at S/PAcclimation; on SSC14 (2Mb) for APP3, APP7, APP10, and APP13 that explained 5.6, 4.7, 2.8, and 3.6% of the genetic variance, respectively. A gene within this QTL region is SYK, involved in the control of immune-receptors. For APP5, a QTL that explained 4.2% of the genetic variance was identified on SSC4 (105Mb), which co-localizes with two genes associated with immune-response: SIKE1and NRAS. For SIV, no QTL was identified. A QTL on SSC7 (130-131Mb) was identified for MH (S/PParity1, 5.1%) and PCV2 (S/PEntry, 34%; S/PAcclimation, 43.4%). These results provide new information on the genetic basis of response to infectious diseases in sows. The identified QTL have the potential to be used to select for improved immune response. The authors thanks PigGen Canada, Genome Canada, and the Canadian Swine Health Board for financial support, and the late Dr. Stephen Bishop for his scientific contributions.
TL;DR: In this article, the authors investigated circulating Natural Antibody (NAb) levels as potential indicators for disease resilience in pigs and found that higher levels of NAb tended to be associated with fewer treatments, lower mortality, higher finishing ADG, and lower day-to-day fluctuations in feed intake.
Abstract:
Disease resilience is the ability of an animal to maintain performance under pathogen exposure but is difficult to select for because breeding populations are raised in biosecure, high-health facilities. Selection for resilience requires an indicator trait that is easy to measure on healthy young animals, heritable, and genetically correlated with resilience. Our objective was to investigate circulating Natural Antibody (NAb) levels as potential indicators for disease resilience in pigs. Data were from a natural polymicrobial disease challenge, in which batches of 60–75 weaned LWxLR barrows were sourced every three weeks (28 batches, 1799 pigs) from healthy multipliers. NAb and total IgG were evaluated by indirect ELISA in blood samples collected around 35 d of age. Disease resilience data were collected until pigs reached market age. All pigs were genotyped on a 650k panel. Genetic parameters were estimated by univariate and bivariate analyses in ASReml4. Single-marker and Bayesian variable selection methods were used for GWAS. Heritability estimates were lower for IgG NAb (0.03–0.22) than for IgM NAb (0.24–0.42) but maternal effects were larger for IgG (0.49–0.58) than for IgM (0.04–0.12). Phenotypically, IgM titers correlated with each other (0.26–0.71), as did IgG titers (0.40–0.81), but correlations between IgM and IgG were low (0.00–0.13). Genetic correlations showed similar patterns, ranging from 0.44–0.99, 0.45–0.84, and -0.30–0.25 for IgG, IgM, and IgG/IgM, respectively. Genetically, higher levels of NAb tended to be associated with fewer treatments, lower mortality, higher finishing ADG, and lower day-to-day fluctuations in feed intake but SE were large. Phenotypically, pigs that reached market age had significantly higher levels of IgG NAb than pigs that died. GWAS identified several genomic regions for NAb levels. In conclusion, levels of circulating NAb in healthy young piglets are potential indicators of polymicrobial disease resilience. Funded by Genome Canada and Alberta, and by USDA-NIFA.