Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus

Abstract

The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD 50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate (P ‫؍‬ 0.02), survival time (P < 0.02), and inflammatory markers (P < 0.01) in the group treated with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4 ؉ and CD8 ؉ T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis. Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.zanamivir ͉ celecoxib ͉ mesalazine

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

“…All virus strains used in this study were isolated from patients ( Table 1). The virus strains H1/415, H7/ AH1 and H7/ZJ1 were used in our previous studies (Chan et al, 2013b;Chen et al, 2013;Li et al, 2009;Zheng et al, 2008). These viruses were propagated in MDCK cells before use.…”

“…Nitazoxanide, an approved antiparasitic agent with broad-spectrum antiviral activity, could reduce the duration of symptoms in patients with uncomplicated influenza virus infection, but the efficacy in patients with severe illnesses has not been reported (Haffizulla et al, 2014). The combination of celecoxib with neuraminidase inhibitors has shown to exert a synergistic effect in a mouse model (Zheng et al, 2008); and naproxen decreases pulmonary titers in infected mice (Lejal et al, 2013), but no human studies have been reported for these clinically approved non-steroidal anti-inflammatory agents.…”

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

“…Uncontrolled virus replication can lead to high titers, and even a modest viral load cannot be maintained for more than a few days before death will occur (61). It is of interest to understand how the kinetics of viral load change with increasing infection rate ␤ ␣ .…”

A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

“…1, 5 Following H5N1 virus infection, systemic and exaggerated release of pro-inflammatory cytokines by rapidly proliferating immune cells and airway epithelial cells results in a cytokine storm and pulmonary damage. A virus-induced cytokine storm has been shown to be highly lethal among young healthy adults, probably due to the strong immune response in these subjects.…”

“…6 Although extensive investigations have centered around studying viral genetics, ecology and geography of viral transmission, and clinical diagnosis and management of H5N1 infection, the dysregulated host immune response is much less defined. 5 Interleukin-17 (IL-17), produced by cells of both the adaptive and innate immune systems, functions as a potent pro-inflammatory cytokine and plays a crucial role in both chronic autoimmune pathogenesis 7 and host defenses against diverse pulmonary pathogens. 8 Previous studies have demonstrated that IL-17 plays a beneficial role in infections by various pathogens, including pulmonary Mycobacterium bovis, Klebsiella pneumonia and vaccinia virus.…”