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Targeting the pro-inflammatory factor CCL2 (MCP-1) with Bindarit for influenza A (H7N9) treatment

View Article: PubMed Central - PubMed

ABSTRACT

Influenza A viruses are important human and animal pathogens. Seasonal influenza viruses cause infections every year, and occasionally zoonotic viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. Three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus were reported in 2013, and there have been several cases reported across South East Asia, and recently in North America. Most patients experience severe respiratory illness, with mortality rates approaching 40%. No vaccine is currently available and the use of antivirals is complicated due to the emergence of drug resistant strains. Thus, there is a need to identify new drugs for therapeutic intervention and disease control. In humans, following H7N9 infection, there is excessive expression of pro-inflammatory factors CCL2, IL-6, IL-8, IFNα, interferon-γ, IP-10, MIG and macrophage inflammatory protein-1β, which has been shown to contribute to fatal disease outcomes in mouse models of infection. In the current study, the potent inhibitor of CCL2 synthesis, Bindarit, was examined as a countermeasure for H7N9-induced inflammation in a mouse model. Bindarit treatment of mice did not have any substantial therapeutic efficacy in H7N9 infection. Consequently, the results suggest that Bindarit may be ill-advised in the treatment of influenza H7N9 infection.

No MeSH data available.


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Effect of Bindarit on pulmonary cell infiltrates following avian IAV H7N9 infection. Mice were i.n. infected with a sub-lethal dose of H7N9 (102.7 PFU) or PBS. Mice were then treated with either Bindarit or vehicle starting on day 1 pi. On day 8 pi mice were killed and BAL fluids collected for analysis with flow cytometry. (a) The total number of leukocytes, (b) the number of macrophages, (c) the number of eosinophils, (d) the number of CD3+ T-cells, (e) the number of CD4+ T cells, and (f) the number of CD8+ T cells were determined. Data are presented as the number of specific type of cells per million total cells. Data are from five mice per group±s.e.m. *P<0.05, **P>0.01, ***P>0.001.
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fig8: Effect of Bindarit on pulmonary cell infiltrates following avian IAV H7N9 infection. Mice were i.n. infected with a sub-lethal dose of H7N9 (102.7 PFU) or PBS. Mice were then treated with either Bindarit or vehicle starting on day 1 pi. On day 8 pi mice were killed and BAL fluids collected for analysis with flow cytometry. (a) The total number of leukocytes, (b) the number of macrophages, (c) the number of eosinophils, (d) the number of CD3+ T-cells, (e) the number of CD4+ T cells, and (f) the number of CD8+ T cells were determined. Data are presented as the number of specific type of cells per million total cells. Data are from five mice per group±s.e.m. *P<0.05, **P>0.01, ***P>0.001.

Mentions: To determine a mechanism for cellular infiltration into the BAL, the was investigated using flow cytometry. Total numbers of leukocytes as well as macrophages, eosinophils, and T cells were not significantly (P<0.01) increased after Bindarit treatment, but were slightly higher than those in mock-treated mice (Figure 8). The effect of Bindarit treatment on cellular infiltration appeared to be weaker after sub-lethal infection than after lethal infection. Interestingly, the number of alveolar macrophages did not change after treatment with Bindarit, despite its known ability to reduce production of monocyte attractant MCP-1/CCL2 in other models.18


Targeting the pro-inflammatory factor CCL2 (MCP-1) with Bindarit for influenza A (H7N9) treatment
Effect of Bindarit on pulmonary cell infiltrates following avian IAV H7N9 infection. Mice were i.n. infected with a sub-lethal dose of H7N9 (102.7 PFU) or PBS. Mice were then treated with either Bindarit or vehicle starting on day 1 pi. On day 8 pi mice were killed and BAL fluids collected for analysis with flow cytometry. (a) The total number of leukocytes, (b) the number of macrophages, (c) the number of eosinophils, (d) the number of CD3+ T-cells, (e) the number of CD4+ T cells, and (f) the number of CD8+ T cells were determined. Data are presented as the number of specific type of cells per million total cells. Data are from five mice per group±s.e.m. *P<0.05, **P>0.01, ***P>0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5382437&req=5

fig8: Effect of Bindarit on pulmonary cell infiltrates following avian IAV H7N9 infection. Mice were i.n. infected with a sub-lethal dose of H7N9 (102.7 PFU) or PBS. Mice were then treated with either Bindarit or vehicle starting on day 1 pi. On day 8 pi mice were killed and BAL fluids collected for analysis with flow cytometry. (a) The total number of leukocytes, (b) the number of macrophages, (c) the number of eosinophils, (d) the number of CD3+ T-cells, (e) the number of CD4+ T cells, and (f) the number of CD8+ T cells were determined. Data are presented as the number of specific type of cells per million total cells. Data are from five mice per group±s.e.m. *P<0.05, **P>0.01, ***P>0.001.
Mentions: To determine a mechanism for cellular infiltration into the BAL, the was investigated using flow cytometry. Total numbers of leukocytes as well as macrophages, eosinophils, and T cells were not significantly (P<0.01) increased after Bindarit treatment, but were slightly higher than those in mock-treated mice (Figure 8). The effect of Bindarit treatment on cellular infiltration appeared to be weaker after sub-lethal infection than after lethal infection. Interestingly, the number of alveolar macrophages did not change after treatment with Bindarit, despite its known ability to reduce production of monocyte attractant MCP-1/CCL2 in other models.18

View Article: PubMed Central - PubMed

ABSTRACT

Influenza A viruses are important human and animal pathogens. Seasonal influenza viruses cause infections every year, and occasionally zoonotic viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. Three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus were reported in 2013, and there have been several cases reported across South East Asia, and recently in North America. Most patients experience severe respiratory illness, with mortality rates approaching 40%. No vaccine is currently available and the use of antivirals is complicated due to the emergence of drug resistant strains. Thus, there is a need to identify new drugs for therapeutic intervention and disease control. In humans, following H7N9 infection, there is excessive expression of pro-inflammatory factors CCL2, IL-6, IL-8, IFN&alpha;, interferon-&gamma;, IP-10, MIG and macrophage inflammatory protein-1&beta;, which has been shown to contribute to fatal disease outcomes in mouse models of infection. In the current study, the potent inhibitor of CCL2 synthesis, Bindarit, was examined as a countermeasure for H7N9-induced inflammation in a mouse model. Bindarit treatment of mice did not have any substantial therapeutic efficacy in H7N9 infection. Consequently, the results suggest that Bindarit may be ill-advised in the treatment of influenza H7N9 infection.

No MeSH data available.


Related in: MedlinePlus