10.5061/DRYAD.72DB024
McGill, Jodi L.
Iowa State University
Guerra-Maupome, Mariana
Iowa State University
Schneider, Sarah
Kansas State University
Data from: Prophylactic digoxin treatment reduces IL-17 production in vivo
in the neonatal calf and moderates RSV-associated disease
Dryad
dataset
2019
2019-03-28T16:49:56Z
2019-03-28T16:49:56Z
en
https://doi.org/10.1371/journal.pone.0214407
78765 bytes
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
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.
Data from Figure 2PBMC cultured with or without digoxin, stimulated with
BRSV or pokeweed mitogen. Data correspond to Figure 2 in manuscript.Figure
2.xlsxData from Figure 1Digoxin concentrations in serum. Data correspond
to Figure 1 in manuscript.Figure 1_ digoxin in serum.xlsxData from Figure
3 - clinical scoresCalves were scored daily based on clinical signs
(fever, cough, respiratory rate, etc.). Data correspond to Figure 3A in
the manuscript.Figure 3A clinical scores.xlsxData from Figure 4NS2 copy
numbers in the lungs of calves on day 10. Corresponds to Figure 4 in the
manuscript.Figure 4 NS2 copy numbers in lung.xlsxData from Figure 5RQ
values from qPCR for various inflammatory cytokines expressed in lung
tissue. Data correspond to Figure 5 in manuscript.Figure 5 qPCR
data.xlsxData from Figure 6Cytospins were done on bronchoalveolar lavage
cells and differential counts were performed. Data correspond to Figure 6
in manuscript.Figure 6 cytospins.xlsxData from Figure 7ELISAs were
performed to detect serum and nasal fluid antibodies, and cells were re
stimulated and cytokines were measured by ELISA. Data correspond to Figure
7 in the manuscript.Figure 7.xlsx