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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.


Related in: MedlinePlus

Effect of Bindarit treatment on weight loss and virus titer 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 orally treated with either Bindarit or vehicle starting at day 1 pi. Mice were monitored for weight loss until day 8 pi (a), when mice were killed and lungs were collected for virus titer analysis with RT-qPCR (b). Virus titers were determined per 5 ng of total RNA extracted from lung homogenates. Time points represent days pi. Data are from five to six mice per group±s.e.m. *P<0.05, **P<0.01.
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fig5: Effect of Bindarit treatment on weight loss and virus titer 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 orally treated with either Bindarit or vehicle starting at day 1 pi. Mice were monitored for weight loss until day 8 pi (a), when mice were killed and lungs were collected for virus titer analysis with RT-qPCR (b). Virus titers were determined per 5 ng of total RNA extracted from lung homogenates. Time points represent days pi. Data are from five to six mice per group±s.e.m. *P<0.05, **P<0.01.

Mentions: No differences in weight loss were observed between mock- and Bindarit-treated mice after i.n. lethal H7N9 infection (105 PFU). The lethal challenge may have been overwhelming and therefore the effect of Bindarit insufficient. Therefore, a study using a sub-lethal dose of virus was performed. Mice were infected 102.7 PFU with a sub-lethal dose of H7N9 and orally treated with Bindarit (70 mg kg−1) twice daily starting at day 1 pi. Mice in both groups lost body weight until day 4 pi. However, on days 5, 6 and 8, Bindarit-treated mice showed a considerable increase in weight loss compared to mock-treated control mice (Figure 5a).


Targeting the pro-inflammatory factor CCL2 (MCP-1) with Bindarit for influenza A (H7N9) treatment
Effect of Bindarit treatment on weight loss and virus titer 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 orally treated with either Bindarit or vehicle starting at day 1 pi. Mice were monitored for weight loss until day 8 pi (a), when mice were killed and lungs were collected for virus titer analysis with RT-qPCR (b). Virus titers were determined per 5 ng of total RNA extracted from lung homogenates. Time points represent days pi. Data are from five to six mice per group±s.e.m. *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5382437&req=5

fig5: Effect of Bindarit treatment on weight loss and virus titer 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 orally treated with either Bindarit or vehicle starting at day 1 pi. Mice were monitored for weight loss until day 8 pi (a), when mice were killed and lungs were collected for virus titer analysis with RT-qPCR (b). Virus titers were determined per 5 ng of total RNA extracted from lung homogenates. Time points represent days pi. Data are from five to six mice per group±s.e.m. *P<0.05, **P<0.01.
Mentions: No differences in weight loss were observed between mock- and Bindarit-treated mice after i.n. lethal H7N9 infection (105 PFU). The lethal challenge may have been overwhelming and therefore the effect of Bindarit insufficient. Therefore, a study using a sub-lethal dose of virus was performed. Mice were infected 102.7 PFU with a sub-lethal dose of H7N9 and orally treated with Bindarit (70 mg kg−1) twice daily starting at day 1 pi. Mice in both groups lost body weight until day 4 pi. However, on days 5, 6 and 8, Bindarit-treated mice showed a considerable increase in weight loss compared to mock-treated control mice (Figure 5a).

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