Emergence of mosaic recombinant strains potentially associated with vaccine JXA1-R and predominant circulating strains of porcine reproductive and respiratory syndrome virus in different provinces of China

Abstract Background Porcine reproductive and respiratory syndrome virus (PRRSV) has caused several outbreaks in China since 2006. However, the genetic diversity of PRRSV in China has greatly increased by rapid evolution or recombination events. Modified live-attenuated vaccines are widely used to control this disease worldwide. Although the risk and inefficacy of the vaccine has been reported, the genetic diversity between epidemic field strains and vaccine strains in China has not been completely elucidated. Methods A total of 293 clinical samples were collected from 72 pig farms in 16 provinces of China in 2015 for PRRSV detection. A total of 28 infected samples collected from 24 pig farms in nine provinces were further selected for immunohistochemical analysis and whole genome sequencing of PRRSV. Phylogenetic analysis and recombination screening were performed with the full genome sequences of the 28 strains and other 623 reference sequences of PRRSV. Results Of 293 clinical samples, 117 (39.93%) were positive for PRRSV by RT-PCR. Phylogenetic results showed that the 28 strains were nested into sublineage 10.5 (classic highly pathogenic [HP]-PRRSV), sublineage 10.6 (HP-PRRSV-like strains and related recombinants), sublineage 10.7 (potential vaccine JXA1-R-like strains), and lineage 9 (NADC30-like strains and recombinants of NADC30-like strains), respectively, suggesting that multiple subgenotypes of PRRSV currently circulate in China. Recombination analyses showed that nine of 28 isolates and one isolate from other laboratory were potential complicated recombinants between the vaccine JXA1-R-like strains and predominant circulating strains. Conclusions These results indicated an increase in recombination rates of PRRSV under current vaccination pressure and a more pressing situation for PRRSV eradication and control in China

Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS

<div><p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS.</p></div

Average percent mouse body weight change after 28 days.

<p>Average percent mouse body weight change after 28 days.</p

Kaplan meier curves of results from efficacy study 4.0 mg/kg qod intraperitoneal injection of guanabenz compared to vehicle control in G93A-SOD1 mice (A) onset of paralysis of male G93A-SOD1 mice, (B) survival of G93A-SOD1 mice, (C) onset of paralysis of female G93A-SOD1 mice, (D) survival of G93A-SOD1 mice, (E) onset of paralysis of all G93A-SOD1 mice, (F) survival of all G93A-SOD1 mice.

<p>Kaplan meier curves of results from efficacy study 4.0 mg/kg qod intraperitoneal injection of guanabenz compared to vehicle control in G93A-SOD1 mice (A) onset of paralysis of male G93A-SOD1 mice, (B) survival of G93A-SOD1 mice, (C) onset of paralysis of female G93A-SOD1 mice, (D) survival of G93A-SOD1 mice, (E) onset of paralysis of all G93A-SOD1 mice, (F) survival of all G93A-SOD1 mice.</p

Guanabenz Efficacy Study Survival Results Summary.

<p>Age of ALS related death in 4.0 mg/kg qod efficacy study and 4.5 mg/kg/day efficacy study.</p

Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS - Fig 1

<p>(A) WST1 absorbance as an indicator of cell viability in a tunicamycin challenge assay using fibroblasts derived from G93A-SOD1 mice. (B) WST absorbance indicator a tunicamycin challenge assay using fibroblasts derived from non-transgenic mice. (C) Tunicamycin EC50s as a function of guanabenz concentration in G93A-SOD1 and non-transgenic mouse fibroblasts.</p

Guanabenz Efficacy Study Paralysis Onset Results Summary.

<p>Age at onset of paresis in 4.0 mg/kg qod efficacy study and 4.5 mg/kg/day efficacy study.</p