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A cross-sectional prospective cohort study including 1026 heifers administered tulathromycin due to high risk of clinical signs of bovine respiratory disease (BRD), measured poor association between BRD clinical outcomes and results of bacterial culture and tulathromycin susceptibility from BRD isolates of deep nasopharyngeal swabs (DNS) and adequate association with viral polymerase chain reaction (PCR) results from nasal swabs. Isolation rates from DNS collected on day-0 and at 1 st BRD-treatment respectively were: Mannheimia haemolytica (10.9% & 34.1%); Pasteurella multocida (10.4% & 7.4%); Mycoplasma bovis (1.0% & 36.6%); and Histophilus somni (0.7% & 6.3%). Prevalence of BRD viral nucleic acid on nasal swabs collected exclusively at 1 st BRD-treatment were: bovine parainfluenza virus type-3 (bPIV-3) 34.1%; bovine viral diarrhea virus (BVDV) 26.3%; bovine herpes virus type-1 (BHV-1) 10.8%; and bovine respiratory syncytial virus (BRSV) 54.1%. Increased relative risk, at 95% confidence intervals, of 1 st BRD-treatment failure was associated with positive viral PCR results: BVDV 1.39 (1.17–1.66), bPIV-3 1.26 (1.06–1.51), BHV-1 1.52 (1.25–1.83), and BRSV 1.35 (1.11–1.63) from nasal swabs collected at 1 st BRD-treatment and culture of M . haemolytica 1.23 (1.00–1.51) from DNS collected at day-0. However, in this population of high-risk feeder heifers, the predictive values of susceptible and resistant isolates had inadequate association with BRD clinical outcome. These results indicate, that using tulathromycin susceptibility testing of isolates of M . haemolytica or P . multocida from DNS collected on arrival or at 1 st BRD-treatment to evaluate tulathromycin clinical efficacy, is unreliable.

Bovine respiratory syncytial virus (BRSV) infection is a part of the bovine respiratory disease complex. This is one of the most significant problems in both the dairy and beef production sector, inflicting severe economic damage to the industry. BRSV manifests clinically as a respiratory syndrome, affecting both upper and lower respiratory tract, including bronchiolitis with dyspnea and wheezing. It has been shown previously that these symptoms caused by IL-4/IL-13 domination in the immune response are associated with an antibody isotype switch to IgE. Prostaglandin production, such as PGE 2 is another factor contributing to the pathogenesis of the disease. In this work we demonstrated the effects of ibuprofen and antiviral fusion protein inhibitor (FPI) separately and combined. We showed the synergistic effect of ibuprofen in combination with FPI on antiviral effects and suppression of PGE 2 , resulting in improved cytoplasmic toll-like receptor recognition and humoral immune responses mediated by antimicrobial peptide in lungs. We also demonstrated a Th1/Th2 balance shift towards a Th2 response in lungs and mediastinal lymph nodes, favorable to IL-4/IL-13 responses. This shift may explain the factors contributing to higher viral loads and the lack of histopathological improvement with ibuprofen administered without FPI. Additionally, we demonstrated that endocannabinoids may play a crucial role as natural regulators of the inflammation, adaptive immune response, and resolution of the inflammatory process.

Background Repurposing off-label drugs during epidemics or pandemics with unknown/known pathogens, particularly when their side effects and complications are already known, can be a strategic approach, as seen during the COVID-19 pandemic. Developing surrogate in vitro experimental models (passage-to-passage), which mimic epidemic/pandemic-like transmission (human-to-human), may enhance this repurposing process. This study evaluates montelukast sodium (MLS), a US FDA-approved leukotriene receptor antagonist for asthma, to explore its potential repurposing antiviral effects against bovine respiratory syncytial virus (BRSV), which has basic similarities to human respiratory syncytial virus (HRSV) as both belong to the Pneumoviridae family. Methods An in vitro serial passage model was developed using MDBK cells infected with a local wild-type strain of BRSV (43TR2018). The cytotoxicity of MLS was assessed via the trypan blue exclusion method, identifying non-toxic concentrations. The impact of MLS on viral spread and infectivity was measured through TCID50 values over 10 passages. Viral loads were confirmed by nested RT-PCR and quantified using qPCR, while apoptosis, necrosis, and nitric oxide production were evaluated through staining and nitrite assays. Data were analyzed using ANOVA and Tukey's test ( p  < 0.05). Results Control cells exhibited 97.16% viability, with 10 µM and 20 µM MLS concentrations maintaining viabilities of 89.2% and 87.3%, respectively. Viral titers significantly decreased at higher concentrations of MLS (up to 99.94% inhibition). Apoptosis rates decreased in MLS-treated cells, and live cell percentages improved, especially at 20 µM. Nitric oxide levels showed no significant differences across groups. Conclusion MLS demonstrated a dose-dependent antiviral effect against BRSV, achieving 99% viral inhibition properties in MDBK cells. These promising results warrant further investigation into the antiviral mechanisms of MLS.

Bovine respiratory syncytial virus (RSV) is a valid model for human RSV and an important bovine pathogen. Very early administration of ibuprofen and GS-561937, a fusion protein inhibitor (FPI), have separately been shown to decrease the severity of bovine RSV. Our aims were to determine how long after RSV inoculation ibuprofen and GS-561937 can be administered with clinical benefit and whether using both was better than monotherapy. We conducted a blinded randomized placebo controlled trial of ibuprofen, GS-561937 (FPI), or combinations of the two initiated at 3 or 5 days after artificial infection with bovine RSV in 36 five to six-week-old Holstein calves (Bos taurus). We measured clinical scores, respiratory rate, and viral shedding daily for 10 days following inoculation. We estimated the average effect for each drug and compared treatment arms using mixed effects models. We found a significant decrease in clinical scores only in the combined treatment arms. This benefit was greater when treatment was initiated at 3 days rather than 5 days post infection with decreased clinical scores and lower respiratory rates at both time points. Ibuprofen alone started on day 3 increased, and FPI with ibuprofen started on day 3 decreased, viral shedding. Dual therapy with Ibuprofen and FPI, on average, decrease clinical severity of illness in a bovine model of RSV when started at 3 and 5 days after infection.

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus. RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical non-steroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase. We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected. We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-γ in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed. One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Clinical scores (p<0.01) and weight gain (p = 0.08) seemed better in the ibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products, and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-γ gene expression in mediastinal lymph nodes. Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen. Ibuprofen decreased PGE2, modulated the immune response, and improved clinical outcomes. However lung histopathology was not affected and viral shedding was increased.

Respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in human infants. Bovine RSV infection of neonatal calves is pathologically and immunologically similar to RSV infection in infants, and is therefore a useful preclinical model for testing novel therapeutics. Treatment of severe RSV bronchiolitis relies on supportive care and may include use of bronchodilators and inhaled or systemic corticosteroids. Interleukin-17A (IL-17) is an inflammatory cytokine that plays an important role in neutrophil recruitment and activation. IL-17 is increased in children and rodents with severe RSV infection; and in calves with severe BRSV infection. It is currently unclear if IL-17 and Th17 immunity is beneficial or detrimental to the host during RSV infection. Digoxin was recently identified to selectively inhibit IL-17 production by antagonizing its transcription factor, retinoid-related orphan receptor γ t (RORγt). Digoxin inhibits RORγt binding to IL-17 and Th17 associated genes, and suppresses IL-17 production in vitro in human and murine leukocytes and in vivo in rodent models of autoimmune disease. We demonstrate here that in vitro and in vivo digoxin treatment also inhibits IL-17 production by bovine leukocytes. To determine the role of IL-17 in primary RSV infection, calves were treated prophylactically with digoxin and infected with BRSV. Digoxin treated calves demonstrated reduced signs of clinical illness after BRSV infection, and reduced lung pathology compared to untreated control calves. Digoxin treatment did not adversely affect virus shedding or lung viral burden, but had a significant impact on pulmonary inflammatory cytokine expression on day 10 post infection. Together, our results suggest that exacerbated expression of IL-17 has a negative impact on RSV disease, and that development of specific therapies targeting Th17 immunity may be a promising strategy to improve disease outcome during severe RSV infection.

Respiratory syncytial virus (RSV) causes severe respiratory disease in calves and human infants. In response to outbreaks, formalin inactivated (FI)-RSV vaccines were developed and found to exacerbate disease following a live RSV infection. We have reproduced vaccination induced disease enhancement in calves and screened various antibody isotypes in bronchoalveolar lavage fluid (BALF) from two studies: one with disease enhancement and another where moderate protection resulted from FI-bovine RSV (BRSV) vaccination. Semi-protected vaccinated calves produced BRSV-specific BALF IgG1, but not IgA and IgG2 prior to infection; whereas, calves with enhanced disease failed to develop BRSV-specific IgG1 in BALF. Ultimately, the formulation and delivery of RSV vaccines influences protective antibody levels in respiratory secretions.

In this study we could demonstrate that heparin (ED50 = 0.32 +/- 0.12 microgram/ml), but not heparan sulphate or chondroitin sulphate C is able to inhibit in vitro infection of cells by respiratory syncytial virus (RSV). In addition, this protective effect of heparin could only be observed, when heparin was present at the time of inoculation. Enzymatic digestion of cell surface glycosaminoglycans with heparinase and heparitinase, but not chondroitin sulphate ABC lyase reduced the effectiveness of RSV-infection. Affinity chromatography experiments, using immobilised heparin further demonstrated that RSV attachment protein G was able to bind specifically to heparin. Therefore heparin-like proteoglycans showed properties required for attachment of RSV to host cells.

Bovine Respiratory Syncytial virus (BRSV) is one of the major infectious agents in the etiology of the bovine respiratory disease complex. BRSV causes a respiratory syndrome in calves, which is associated with severe bronchiolitis. In this study we describe the effect of treatment with antiviral fusion protein inhibitor (FPI) and ibuprofen, on gene expression in lung tissue of calves infected with BRSV. Calves infected with BRSV are an excellent model of human RSV in infants: we hypothesized that FPI in combination with ibuprofen would provide the best therapeutic intervention for both species. The following experimental treatment groups of BRSV infected calves were used: 1) ibuprofen day 3–10, 2) ibuprofen day 5–10, 3) placebo, 4) FPI day 5–10, 5) FPI and ibuprofen day 5–10, 6) FPI and ibuprofen day 3–10. All calves were infected with BRSV on day 0. Daily clinical evaluation with monitoring of virus shedding by qRT-PCR was conducted. On day10 lung tissue with lesions (LL) and non-lesional (LN) was collected at necropsy, total RNA extracted, and RNA sequencing performed. Differential gene expression analysis was conducted with Gene ontology (GO) and KEGG pathway enrichment analysis. The most significant differential gene expression in BRSV infected lung tissues was observed in the comparison of LL with LN; oxidative stress and cell damage was especially noticeable. Innate and adaptive immune functions were reduced in LL. As expected, combined treatment with FPI and Ibuprofen, when started early, made the most difference in gene expression patterns in comparison with placebo, especially in pathways related to the innate and adaptive immune response in both LL and LN. Ibuprofen, when used alone, negatively affected the antiviral response and caused higher virus loads as shown by increased viral shedding. In contrast, when used with FPI Ibuprofen enhanced the specific antiviral effect of FPI, due to its ability to reduce the damaging effect of prostanoids and oxidative stress.

Non-steroidal anti-inflammatory drugs (NSAID) are not recommended for use against pneumonia in humans, but are commonly utilised against bovine respiratory disease. This study aimed to determine if the use of NSAIDs in the early phase of bovine respiratory syncytial virus (BRSV)-infection limits pulmonary inflammation. Four to nine-week old calves were infected with BRSV by aerosol and were treated with either meloxicam intravenously on day (D)4 (n = 5, MEL), acetylsalicylat-DL-lysin intravenously on D4 and D5 (n = 5, ASA), or were left untreated as controls (n = 5, CTR). Clinical signs were monitored daily until necropsy on D7, BRSV-RNA was detected in nasal swabs and bronchoalveolar lavage (BAL) by RT-qPCR, inflammatory cells and proteins were identified in BAL by cytology and label-free quantitative mass spectrometry-based proteomics, respectively, and oxylipids were quantified in BAL and plasma by liquid chromatography tandem mass spectrometry with triple quadrupole mass detectors. The calves developed mild to moderate signs of respiratory disease and, with the exception of one MEL-treated and one ASA-treated calf, limited lung lesions. None of the treatments had a significant effect on virus replication, clinical signs or lung lesion extent. Relative to controls, both treatments initially induced a downregulation of proteins in BAL. Immunoglobulin (Ig)-related proteins, such as the Ig kappa and lambda locus and the joining chain of IgA and IgM, were downregulated in MEL-treated calves compared to controls. In addition, meloxicam induced an increased neutrophil influx in BAL in response to BRSV, possibly related to a reduction in plasma prostaglandin, and to a downregulation of The Liver X Receptor/ Retinoid X Receptor (LXR/RXR), the Farnesoid X Receptor (FXR)/RXR and the 24-Dehydrocholesterol Reductase (DHC24) signalling pathways in the lung. The risk of NSAIDs to increase neutrophil activity during stimulation with BRSV or other toll-like receptor 4 agonists needs to be investigated further. Since augmented neutrophil responses can be detrimental, the results of the present study do not support the use of NSAIDs to prevent the clinical expression of BRSV-infection.