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Browsing by Author "Lebedev, Maxim"

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    Analysis of lung transcriptome in calves infected with Bovine Respiratory Syncytial Virus and treated with antiviral and/or cyclooxygenase inhibitor
    Lebedev, Maxim; McEligot, Heather A.; Mutua, Victoria N.; Walsh, Paul; Carvallo, Francisco R.; Gershwin, Laurel J. (2021-02-18)
    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.
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    A randomized controlled trial comparing non-steroidal anti-inflammatory and fusion protein inhibitors singly and in combination on the histopathology of bovine respiratory syncytial virus infection
    Carvallo, Francisco R.; Walsh, Paul; Lebedev, Maxim; Mutua, Victoria N.; McEligot, Heather A.; Bang, Heejung; Gershwin, Laurel J. (PLoS, 2021-06-01)
    Bovine respiratory syncytial virus (RSV) has substantial morbidity in young calves, and closely parallels human RSV in infants. We performed a randomized controlled trial in five to six-week-old Holstein calves (Bos taurus). comparing fusion protein inhibitor (FPI) and nonsteroidal anti-inflammatory drug (NSAID) singly and in combination at three and five days after experimental BRSV infection. Thirty-six calves received one of six treatments; Ibuprofen started on day 3, Ibuprofen started on day 5, FPI started on day 5, FPI and Ibuprofen started on day 3, FPI and Ibuprofen started on day 5, or placebo. We have previously reported significant clinical benefits when combined FPI and NSAID treatment was started at three and five days after bovine RSV infection. Necropsy was performed on Day 10 following infection and hematoxylin and eosin staining was performed on sections from each lobe. Histology was described using a four-point scale. We performed canonical discrimination analysis (CDA) to determine the structural level where differences between treatments occurred and mixed effects regression to estimate effect sizes. Separation from placebo was maximal for dual therapy at the levels of the alveolus, septum, and bronchus in CDA. We found that the clinical benefits of combined FPI and NSAID treatment of BRSV extend at least partially from histopathological changes in the lung when treatment was started three days after infection. We found decreased lung injury when ibuprofen was started as monotherapy on day 3, but not day 5 following infection. Combined therapy with both an FPI and ibuprofen was always better than ibuprofen alone. We did not prove that the clinical benefits seen starting FPI and ibuprofen five days after infection can be solely explained by histopathological differences as identified on H&E staining.