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URL: https://pubmed.ncbi.nlm.nih.gov/31293574/

⇱ Ponatinib Protects Mice From Lethal Influenza Infection by Suppressing Cytokine Storm - PubMed

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Abstract

Excessive inflammation associated with the uncontrolled release of pro-inflammatory cytokines is the main cause of death from influenza virus infection. Previous studies have indicated that inhibition of interferon gamma-induced protein 10 (IP-10), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), or their cognate receptors has beneficial effects. Here, by using monocytic U937 cells that capable of secreting the three important cytokines during influenza A virus infection, we measured the inhibitory activities on the production of three cytokines of six anti-inflammatory compounds reported in other models of inflammation. We found that ponatinib had a highly inhibitory effect on the production of all three cytokines. We tested ponatinib in a mouse influenza model to assess its therapeutic effects with different doses and administration times and found that the delayed administration of ponatinib was protective against lethal influenza A virus infection without reducing virus titers. Therefore, we suggest that ponatinib may serve as a new immunomodulator in the treatment of influenza.

Keywords: cytokine storm; immunomodulator; influenza A virus; ponatinib; pro-inflammatory cytokine.

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Figures

👁 Figure 1
Figure 1
Ponatinib was identified to inhibit the production of three important cytokines associated with influenza-induced cytokine storm. U937 cells were infected with influenza A virus A/PuertoRico/8/1934 (MOI = 0.1) in the presence or absence of serially diluted of each compound and incubated at 37°C for 48 h. The supernatants were harvested, and concentrations of IL-8, IP-10, and MCP-1 were measured by AlphaLISA. Cell viability was also determined using Cell Titer-Glo. The kinetic curves of each compound were made using Prism v.5 software (GraphPad Software, San Diego, CA). The values represent the means ± S.D. of duplicate samples from three independent experiments.
👁 Figure 2
Figure 2
Ponatinib reduces influenza A virus-induced mortality in mice. BALB/c mice of 6–8 weeks old were infected with 500 TCID50 of influenza A virus (A/PR/8/34) by intranasally. Two hours later, 4 groups of mice (n = 10) were simultaneously treated orally with 25, 15, 5 mg/kg/d of ponatinib, or placebo. Survival rate (A) and body weight loss (B–D) were monitored daily until day 20 post-infection. The data are representative of at least three independent experiments.*p < 0.05; ***p <0.001.
👁 Figure 3
Figure 3
Delayed administration of ponatinib enhances protection against lethal infection in mice. (A) Experimental setup for optimization of drug administration timing. Mice were infected as described in Figure 2 but treated with ponatinib (15 mg/kg) starting on days 1, 2, 3, or 4 post-infection until day 6 post-infection. Survival rate (B) and weight loss (C–F) were monitored daily until day 20 post-infection. The data are representative of at least three independent experiments. *p < 0.05; **p < 0.01; ***p <0.001.
👁 Figure 4
Figure 4
Ponatinib suppresses neutrophils infiltration in the lungs of mice with lethal infection. Mice were infected as described in Figure 2. Starting with day 3, daily administration of placebo or ponatinib (15 mg/kg) was given orally. (A) Hematoxylin & eosin-stained mouse lung sections (scale bar 200 μm) harvested at day 7 post-infection. (B) BALFs were collected from placebo and ponatinib-treated mice (n = 3 per group at each time point) starting day 3 post-infection to monitor total cell counts (mean ± SEM) on days 5 and 7 post-infection. The data are representative of at least three independent experiments.*p < 0.05; **p < 0.01.
👁 Figure 5
Figure 5
Ponatinib attenuates pro-inflammatory cytokines in the lungs of mice with lethal infection. Mice were infected as described in Figure 2. Starting with day 3, daily administration of placebo or ponatinib (15 mg/kg) was given orally. Inflammatory cytokine/chemokine concentrations in BALF from mice at day 5 and day 7 post-infection (n = 3 per group at each time point) were measured. (A) IL-6, IL-10, IL-12(P40), IL-12(P70), IL-17A, Eotaxin, G-CSF, KC, MCP-1, MIP-1a, MIP-1β, TNF-α, and CCL5 concentrations were quantified by multiplex assay and IP-10 concentrations were measured by AlphaLISA. IFN levels in (B) BALF and (C) serum were measured by ELISA. (D) Viral titers in BALF taken on day 5 and 7 post-infection were measured by TCID50 assay using MDCK cells (n = 3 per group at each time point). The data are representative of two independent experiments.*p < 0.05; **p < 0.01; ***p < 0.001.
👁 Figure 6
Figure 6
Simultaneous administration of ponatinib and infection of mice promotes viral proliferation. Mice were infected as described in Figure 2. Starting with day 0, daily administration of placebo or ponatinib (15 mg/kg) was given orally. Inflammatory cytokine/chemokine concentrations in BALF from mice at day 0, 2, 3, 5, and 7 post-infection were measured. (A) IL-6, IL-10, Eotaxin, G-CSF, MCP-1, MIP-1β, TNF-α, and CCL5 concentrations were quantified by multiplex assay and IP-10 concentrations were measured by AlphaLISA. IFN levels in BALF (B) and serum (C) were measured by ELISA. (D) Viral titers in BALF collected at day 0, 2, 3, 5, and 7 post-infection were measured by TCID50 assay using MDCK cells (n = 3). The data are representative of two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001.

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