Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR

A large body of evidence indicates that metazoan innate immunity is regulated by the nervous system, but the mechanisms involved in the process and the biological importance of such control remain unclear. We show that a neural circuit involving npr-1, which encodes a G protein-coupled receptor (GPCR) related to mammalian neuropeptide Y receptors, functions to suppress innate immune responses. The immune inhibitory function requires a guanosine 3',5'-monophosphate-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we show that npr-1- and gcy-35-expressing sensory neurons actively suppress immune responses of nonneuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 shows an enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/p38 mitogen-activated protein kinase signaling pathway. These results present evidence that neurons directly control innate immunity in C. elegans, suggesting that GPCRs may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate immune responses.     

The prevention of attachment and the detachment effects of a novel combination of fipronil, amitraz and (S)-methoprene for Rhipicephalus sanguineus and Dermacentor variabilis on dogs

A novel combination of fipronil, amitraz and (S)-methoprene (CERTIFECT?, Merial Limited, GA, USA) was evaluated for the prevention of attachment of ticks and its ability to cause detachment of ticks. For the two prevention of attachment studies, 20 purpose-bred beagles were allocated each to two equal groups based on pretreatment tick counts (treated and untreated). Each dog was exposed to 50 adult Rhipicephalus sanguineus and Dermacentor variabilis weekly starting 24h after treatment. In study 1 infestations with R. sanguineus were discontinued after Day 7 but continued to Day 28 for D. variabilis in both studies. Counts of ticks by species were made 2, 4 and 24h after exposure to ticks. Ticks not attaching to dogs were evaluated for viability. For the evaluation of detachment study, 16 purpose-bred beagles were allocated each to two equal groups based on pretreatment tick counts (treated and untreated). Each dog was infested with 50 unfed R. sanguineus and D. variabilis adults on Day -2. Ticks were thumb counted without removal on all dogs on Day -1, and at 4, 12, and 24h after treatment. Ticks were counted and removed at 48 h after treatment. Dogs treated with the novel combination had significantly (p<0.05) lower total numbers of attached R. sanguineus and D. variabilis than untreated controls at 4h through Day 7. For R. sanguineus, percent reduction of attachment at 24h after infestation through Day 29 ranged from 94.5% to 100%. For D. variabilis, the percent reduction of attachment at 24h through Day 22 was above 98.0%. These studies demonstrate that novel combination can disrupt attachment of R. sanguineus and D. variabilis for up to 28 days following treatment. Of those ticks that are exposed to the treatment, even if they do not attach to the dog and remain in the environment, greater than 90% (p<0.05) die within 24h for 2-3 weeks following treatment. Also, for those dogs infested with ticks at the time of treatment, the novel combination causes significant detachment (p<.05) starting at 12h and reaching 98.9% by 48 h after treatment. This product provides an effective means for controlling ticks infesting dogs and limiting the spread of tick transmitted diseases. Additionally, the mortality of ticks exposed to CERTIFECT will reduce infestation of the dog's environment.     

Hereditary xanthinuria in a goat

A 2‐year‐old mixed breed goat was presented for a 1‐day history of anorexia and 1 week of weight loss. Serum biochemistry disclosed severe azotemia. Abdominal ultrasound examination showed decreased renal corticomedullary distinction, poor visualization of the renal pelves, and dilated ureters. On necropsy, the kidneys were small, the pelves were dilated, and the medulla was partially effaced by variably sized yellow nephroliths. Histologically, cortical and medullary tubules were distended by yellow‐brown, multilayered crystals. Stone composition was 100% xanthine. Exonic sequencing of xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) identified 2 putative pathogenic variants: a heterozygous XDH p.Leu128Pro variant and a homozygous MOCOS p.Asp303Gly variant. Variant frequencies were determined in 7 herd mates, 12 goats undergoing necropsy, and 443 goats from genome databases. The XDH variant was not present in any of these 462 goats. The MOCOS variant allele frequency was 0.03 overall, with 3 homozygotes detected. Hereditary xanthinuria is a recessive disorder in other species, but the XDH variant could be causal if the case goat is a compound heterozygote harboring a second variant in a regulatory region not analyzed or if the combination of the XDH and MOCOS variants together abolish XDH activity. Alternatively, the MOCOS variant alone could be causal despite the presence of other homozygotes, because hereditary xanthinuria in humans often is asymptomatic. Ours is the first report describing the clinical presentation and pathology associated with xanthine urolithiasis in a goat. The data support hereditary xanthinuria, but functional studies are needed to conclusively determine the causal variant(s).