20 Young Scholar Talk PHD: Implications of Histone Toxicity and Complement System Activity in Sheep and Cattle During Immunomodulatory States Including Respiratory Disease and Pregnancy
Authors: Flores Victor V 
Published: October 2022

Abstract
The immunostimulatory and toxic effects of extracellular histones have been demonstrated in humans and rodents suffering from acute respiratory distress syndrome and acute lung injury. Accumulating evidence suggests intricate interactions between extracellular histones and immune complement system proteins occur as a regulatory mechanism. However, limited information is available on the interactions of complement system activity and histone toxicity during immunomodulatory events in livestock. Therefore, our current research is aimed at investigating the contributions of histone toxicity and complement system activity in relation to respiratory disease and pregnancy in wild and domestic sheep and cattle. In an initial study, feedlot heifers were evaluated for protective capacity against extracellular histones and complement activity related to subsequent disease outcomes. At feedlot arrival, serum samples were collected from 118 heifer calves (BW 229 ± 2.4 kg) and subjected to a histone toxicity assay and a 50% hemolytic complement activity assay. Heifers were retrospectively assigned as either never receiving treatment with antibiotics for bovine respiratory disease (NT; n = 80) or calves that died from bovine respiratory disease within 1 wk of entering the feedlot (DA; n = 9). Serum from DA animals was less (P &lt; 0.001) protective against histone toxicity compared to NT heifers. Likewise, complement activity of DA animals was reduced (P &lt; 0.05) compared to NT animals. These results suggest cattle predisposed to severe cases of respiratory disease have impaired complement system activity presumably leading to reduced protection against histone toxicity. In a second study, wild Alaskan Dall sheep (Ovis dalli dalli) and domestic sheep (Ovis aries) were evaluated for susceptibility to histone toxicity. Serum was collected from Debouillet sheep (n = 150) with no clinical signs of illness and serum of wild Alaskan Dall sheep (n = 135) was collected from live capture and release animals. Dall sheep serum was less (P &lt; 0.05) protective against histone toxicity compared to Debouillet sheep. Low protection against histone toxicity may be related to higher reported disease states for wild sheep. Furthermore, recognizing that disease modulates immune function, it is also recognized pregnancy relies on immune system activation. Therefore, pregnant sheep serum was evaluated to determine the effect of histone toxicity and complement system activity. Serum was collected from Debouillet ewes (n = 8) and analyzed for histone toxicity protectiveness and complement activity. Serum was collected from ewes prior to breeding (d -0) and at d 1 and 17 of the estrous cycle. Serum protective capacity against histones and complement activity was not significantly different on d -0 compared to d 1 and d 17. Collectively, these data implicate the toxic effect of extracellular histones and complement system activity during respiratory disease states with less obvious observations during pregnancy.