Authored by Gifford CA*
Abstract
Bovine respiratory disease complex (BRDC) is a major health issue facing the feedlot industry and is the leading cause of morbidity and mortality in feedlot cattle. The genome of bovine viral diarrhea virus (BVDV), a common agent in BRDC, contains an amino terminus protease (Npro)that inhibits the type I interferon (IFN) response in vitro, however in vivo work indicates that thetype I IFN response is activated during BVDV infection. Dietary mineral status has been implicated in BRDC susceptibility in calves during shipping, but little is known regarding mineral supplementation and the IFN response. To determine if Cu deficiency or natural exposure to BVDV1b inhibits IFN signaling in vivo, Cu deficient (n=6) or control (n=6) calves were infected with BVDV1b and Mannheimia haemolytica (MH). Steady-state mRNA levels of MX1, ISG15, and RTP4 were determined in peripheral blood leukocytes prior to BVDV1b exposure (day -4), prior to MH challenge (0 h), and 12 h and 24 h after MH challenge. Changes in gene expression are relative to the average of day -4 values was quantified. No mineral effects were detected (P>0.10) so mineral deficient and supplemented groups were pooled. A significant time effect (P<0.05) for all interferon stimulated genes was detected. At 0h, ISG15 mRNA expression increased 44-fold and remained elevated over 60-fold for 12 h and 24 h (P<0.01). Likewise, RTP4 and MX1 increased at 12 h (P<0.05) after BRD challenge. Data suggests that regardless of Cu status, the type I interferon pathway remains active after being challenged with BVDV1b and MH in vivo.
Keywords: BVDV; Bovine respiratory disease; Interferon; Mineral; Shipping fever
Introduction
Bovine respiratory disease complex (BRDC) is a major health and economic issue for feedlots in the United States. Bovine respiratory disease is responsible for roughly $800 to 900 million dollars in lost revenue each year due to decreased feed efficiency, medicinal costs, and eat [1]. In 2011, an estimated 16.2% of all cattle in the United States were affected by respiratory disease, and 87.5% of those animals required treatment for the disease [2]. Treatment costs for BRDC have increased to $23.60 per case which is double the cost observed in 1999 [2]. Bovine respiratory disease typically results from a co-infection of both viral and bacterial pathogens. Common viral agents include bovine viral diarrhea virus type 1 and 2 , parainfluenza type 3, and infectious bovine rhinotracheitis, bacterial agents include, Mannheimia haemolytica, Pasturella multocida, and Haemophilus [3] In Oklahoma, bovine viral diarrhea virus (BVDV) and Mannheimia haemolytica are the two most common pathogens in BRDC cases [4] Viral infections activate the type I IFN pathway which in turn stimulates transcription of interferon stimulated genes [5]. Host pattern-recognition receptors (PRR) identify pathogen-associated molecular patterns (PAMPS) and stimulate innate immune activation and IFN production. Multiple PRR exist and are found in various cellular domains leading to a variety of pathways that can stimulate IFN production, but these pathways appear to converge at interferon regulatory factors- (IRF) 3 and -7 [6]. Work utilizing in vitro models demonstrates that BVDV prevents binding of IRF-3 to DNA, thus inhibiting type I IFN production [7,8] demonstrated that the NPro protein of BVDV blocks induction of IFN-β by degrading IRF-3.Collectively, these results suggest that BVDV can disrupt the type I IFN pathway, thereby reducing the production of IFN, but these works were conducted strictly in vitro only. Conversely, studies which expose cattle in vivo to laboratory cultured BVDV appear to maintain type I IFN production Bovine respiratory disease complex is most often observed in cattle being shipped, and studies have suggested that mineral supplementation can alleviate rates of BRDC in shipped cattle. For example, calves fed organic trace mineral supplements were found to have higher concentrations of eosinophils, suggesting that they would be better able to cope with an inflammatory response [9]. Furthermore, addition of organic trace minerals to diets in feedlot cattle decreased the percentage of sick animals that needed second treatment of antibiotics for bovine respiratory disease [10]. This may indicate that while mineral status does not affect rate of morbidity, mineral deficiency potentially impairs the innate immune response. However, the effects of dietary minerals status on the type I IFN response have not been evaluated.
The objectives of the current study were to evaluate the type I IFN response in calves exposed to BVDV via exposure to a persistently infected (PI) calf and determine the effects of copper deficiency on type I IFN activation during viral exposure.
Materials and Methods
Animals
All procedures for this experiment were approved by the Oklahoma State University Institutional Animal Care and Use Committee (Animal Care and Use Protocol AG-12-5) Twelve bull calves were selected from an Angus based commercial cow herd. Calves were individually tagged, surgically castrated, and vaccinated for clostridial pathogens (Covexin 8; Merck Animal Health, Summit, NJ) at the ranch of origin 80 days prior to the start of the experiment. Blood samples from all calves were seronegative to BVDV at 80 days and 24 days prior to the start of the experiment. All calves were tested for persistent infection of BVDV by immunohistochemical analysis (Oklahoma Animal Disease and Diagnostic Laboratory,Stillwater, OK). Eleven days prior to the start of the experiment, calves were vaccinated for clostridial pathogens, infectious bovine keratoconjunctivitis (Autogenous Bacterin; Newport Laboratories, Worthington, MN) and viral pathogens, excluding BVDV, (Inforce; Zoetis,Florham Park, NJ). Calves were also treated for internal and external parasites (Ivermax Plus;Norbrook Laboratories, Lenexa, KS). Tilmicosin phosphate (300 mg per mL) was administered at the rate of 1.5 mL per 45.4 kg of BW (Micotil; Elanco Animal Health, Indianapolis, IN) and every calf was given a fly tag (Corathon; Bayer, Shawnee Mission, KS). Calves were then transported to the Animal Science Equine Center at Oklahoma State University for a 6-day weaning period.
After weaning, calves were transported to the Nutrition and Physiology Research Center (NPRC) at Oklahoma State University 5 days prior to the initiation of the experiment. Upon arrival calves were weighed, and, using body weight and initial antibody titers to BVDV and MH, calves were allocated to experimental treatments of control (CONT) or copper deficient (CuDef). For 5 days calves were placed in individual metabolic stanchions with automatic waters and individual feed troughs to allow for adaptation. Calves were then randomly assigned to individual 3.05 x 3.66 m slatted floor pens for 42 days (day -46 of experiment; day 0=MH challenge) with access to automatic water bowls and individual feed bunks. During the 42day period prior to BRDC challenge, calves were fed diets that were not mineral supplemented or mineral supplemented (described below). The BVDV and MH challenge was conducted as described by [4] with minor modifications. Briefly, pre-BVDV peripheral blood leukocyte (PBL) samples were collected on day -4 (day 0=MH challenge), calves were comingled in a common pasture for 4 days with a persistently infected (PI) animal [11]. On day 0 calves were gathered and placed in metabolic stanchions and pre-MH challenge PBL samples were taken. All calves received 10 mL of a solution containing 6 x 10^9 CFU of MH serotype 1 that was reconstituted and grown prior to the challenge as described by Mosier et al. Mannheimia haemolytica was delivered via intratracheal bronchoalveolar by a licensed veterinarian (Dowling et al., 2002).
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