Bovine respiratory disease (BRD) remains the greatest challenge facing the beef industry. Calves affected by BRD can manifest illness ranging from subclinical infection to acute death. In pathologies similar to BRD, extracellular histones have been implicated as major contributors to lung tissue damage. Histones are basic proteins responsible for DNA organization in cell nuclei, however when released extracellularly during cell injury or via neutrophil activation they become cytotoxic. Cattle suffering severe cases of BRD demonstrate reduced capacity to protect against the cytotoxic effects of histones, however, the protective mechanism(s) of serum remain(s) unknown. Therefore, the objective was to identify components within serum that contribute to protection against histone toxicity. Serum proteins from animals considered protective (P; N = 4) and nonprotective (NP; N = 4) against the toxic effects of histones were precipitated by the addition and incubation of exogenous histones. Proteins that interact with histones from both groups were isolated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified via label free "shotgun" proteomics. Sixteen candidate proteins increased by ≥2-fold change in P vs. NP animals were identified, with several associated with the complement system. A subsequent study was conducted to evaluate complement system activity and serum protective capacity against exogenous histones in feedlot heifers. Serum samples were collected from 118 heifer calves (BW at arrival = 229 ± 2.4 kg) at feedlot arrival. Animals were retrospectively assigned to groups consisting of: calves not requiring treatment with antibiotics for BRD (CONT; N = 80), calves treated once (1TRT; N = 21), calves treated twice (2TRT; N = 5), calves treated thrice (3TRT; N = 3), or calves that died from BRD within 1 wk of entering the feedlot (DA; N = 9). Serum from DA animals was less protective than CONT (P = 0.0005) animals against histone toxicity. Complement activity of DA animals was reduced compared to CONT (P = 0.0044) animals. Additionally, the use of both assays as a ratio resulted in increased ability to detect DA animals. Results suggest that cattle predisposed to severe cases of respiratory disease may have impaired complement activity presumably contributing to reduced protective capacity against histone toxicity.
Keywords: bovine respiratory disease; cattle; complement system; extracellular histones; histone toxicity.
Bovine respiratory disease (BRD) remains the leading cause of feedlot calf sickness and death. In respiratory disease affecting humans and mice, major tissue damage is caused by release of histones. Histones are proteins found in the nucleus of cells that condense DNA, however, cells that become damaged release histones extracellularly. Research has shown that calves with severe cases of BRD are less able to protect against the toxic effects of histones residing outside of the cell. It is speculated that components within the blood may interact with histones and confer protection from histone toxicity. This study evaluated serum from protective and nonprotective cattle against histone toxicity and identified 16 proteins that were elevated in protective animals. Several proteins were associated with the complement system of the innate immune system. To evaluate immune complement activity and protective capacity against histone toxicity, serum was collected from heifers at feedlot arrival. Calves suffering from a severe case of BRD demonstrated reduced capacity to protect against histone toxicity. Complement activity of calves severely affected with BRD was reduced as well. Results suggest that cattle susceptible to severe cases of BRD may have impaired complement activity likely contributing to reduced protective capacity against histone toxicity.
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