Abstract
PRRSV infection in third-trimester pregnant sows can lead to fetal death and abortions, although the mechanisms triggering these effects are not well understood. Since resistant and susceptible fetuses can coexist in the same litter, we propose that there may be differential mechanisms used by some fetuses to evade infection and/or disease progression. Our objectives were to investigate possible differences in the metabolome of PRRSV-infected and non-infected fetuses, as well as the interaction of altered intrauterine growth development and PRRSV infection to elucidate possible causes of fetal death following PRRSV infection. Near-term serum samples collected from fetuses on gestation day 106, 21 days post PRRSV-2 infection, were processed by direct flow injection mass spectrometry (DI-MS) and nuclear magnetic resonance (NMR) techniques. Experiment one investigated disease progression with 24 fetuses selected from each of four phenotypic groups: fetuses from non-inoculated gilts (CTRL); fetuses from inoculated gilts that escaped infection (UNINF); infected high viral load viable fetuses (INF); and infected high viral load meconium-stained fetuses (MEC). Experiment two investigated the interaction of intrauterine growth retardation (IUGR) and PRRSV infection by analyzing differences among: non-infected normal development (CON-N); CON-IUGR; PRRS infected normal development (PRRS-N); and PRRS-IUGR. Univariate and multivariate (PCA, PLS-DA) statistics determined group differences among various contrasts, and the most important metabolites associated with disease progression and fetal development. Significant differences in the metabolome were observed, especially between PRRSV-negative fetuses (CTRL and UNINF) and MEC fetuses, while INF fetuses appear to span both groups. The two metabolites with highest variable importance in projection (VIP) scores related to disease progression were alpha-aminoadipic acid (alpha-AAA) and kynurenine (KYN), having the highest concentration in MEC and INF fetuses, respectively, compared to CTRL and UNINF. In experiment two, non-IUGR fetuses were found to have increased levels of lysoPCs, PCs and amino acids compared to IUGR fetuses, while the near complete absence of lysoPCs and PCs in IUGR fetuses, even during infection, indicate a distinctive response to infection compared to non-growth retarded fetuses. Possible markers of PRRSV fetal susceptibility, such as alpha-AAA, kynurenine and lysoPCs, are presented and discussed.
Highlights
In medical research, the development of global untargeted metabolomic techniques has provided tremendous insight into the cellular and biochemical processes occurring in healthy individuals, or those subjected to physiological stresses, neoplasia or infective diseases
Partial Least Squares Discriminant Analysis (PLS-DA) (2 components, R2 = 0.68, Q2 = 0.54) where clear differences (P < 5e-04; 0/2,000 permutations) in the metabolome were observed for the PRRSV negative groups (CTRL and UNINF) compared to the meconium-stained fetuses (MEC) fetuses, while the metabolome of HVL-VIA fetuses spanned both groups (Figure 1A)
The metabolites with the greatest contribution to disease progression and group separation were kynurenine and aminoadipic acid, being of highest concentration in MEC and HVL-VIA fetuses compared to UNINF and control gilts (CTRL) (Figure 1B)
Summary
The development of global untargeted metabolomic techniques has provided tremendous insight into the cellular and biochemical processes occurring in healthy individuals, or those subjected to physiological stresses, neoplasia or infective diseases. Pregnant gilts experience minor symptoms but have a significant endometritis, vasculitis and immune response following PRRSV infection (Ladinig et al, 2014b,c; Novakovic et al, 2016) that may impact the efficiency of the placenta and thereby alter fetal metabolomics and compromise growth and viability. Previous large-scale research allowing the categorization of fetuses according to their phenotypic responses identified differences in genomic (e.g., fetal SNPs related to thymus viral load and fetal viability) (Yang et al, 2016) and transcriptomic (e.g., increased TREM1 signaling as disease progresses) (Wilkinson et al, 2016) profiles of susceptible and resilient fetuses, indicating that events occurring within the fetal compartment are important to the final outcome. It has been observed that intrauterine growth-retarded (IUGR) fetuses, fetuses born with lower body weight relative to brain weight (i.e., “brain sparing”) when compared to its siblings, possess lower viral concentration after maternal inoculation than fetuses experiencing normal intrauterine growth (Ladinig et al, 2014a)
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