No abstract

Influenza, a respiratory disease caused by influenza viruses, still represents a major threat to humans and several animal species. Besides vaccination, only two classes of drugs are available for antiviral treatment against this pathogen. Thus, there is a strong need for new effective antivirals against influenza viruses. Here, we tested Ladania067, an extract from the leaves of the wild black currant (Ribes nigrum folium) for potential antiviral activity against influenza A virus in vitro and in vivo. In the range of 0–1 mg/ml the extract showed no cytotoxic effect on three cell lines and a CC50 of 0.5 ± 0.3 mg/ml, on peripheral blood mononuclear cells. Furthermore, the extract did not influence the proliferative status of human lymphocytes. In contrast, Ladania067 was highly effective (EC50 value: 49.3 ± 1.1 ng/ml) against the human pandemic influenza virus strain A/Regensburg/D6/09 (H1N1). The extract exhibited an antiviral effect when the virus was pre-incubated prior to infection or when added directly after infection. No antiviral effect was found when infected cells were treated 2, 4, or 8 h after infection, indicating that Ladania067 blocks a very early step in the virus infection cycle. In the mouse infection model we were able to demonstrate that an intranasal application of 500 μg Ladania067 inhibits progeny virus titers in the lung up to 85% after 24 h. We conclude that the extract from the leaves of the wild black currant may be a promising source for the identification of new molecules with antiviral functions against influenza virus.

Influenza A virus (IAV) infection is often followed by secondary bacterial lung infection, which is a major reason for severe, often fatal pneumonia. Communityassociated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains such as USA300 cause particularly severe and difficult-to-treat cases of IAV-associated pneumonia. CA-MRSA strains are known to produce extraordinarily large amounts of phenol-soluble modulin (PSM) peptides, which are important cytotoxins and proinflammatory molecules that contribute to several types of S. aureus infection. However, their potential role in pneumonia has remained elusive. We determined the impact of PSMs on human lung epithelial cells and found that PSMs are cytotoxic and induce the secretion of the proinflammatory cytokine interleukin-8 (IL-8) in these cells. Both effects were boosted by previous infection with the 2009 swine flu pandemic IAV H1N1 strain, suggesting that PSMs may contribute to lung inflammation and damage in IAV-associated S. aureus pneumonia. Notably, the PSM-producing USA300 strain caused a higher mortality rate than did an isogenic PSM-deficient mutant in a mouse IAV-S. aureus pneumonia coinfection model, indicating that PSMs are major virulence factors in IAV-associated S. aureus pneumonia and may represent important targets for future anti-infective therapies.KEYWORDS influenza, pneumonia, Staphylococcus aureus, toxins B acterial pneumonia is a severe disease that can be caused by bacterial superinfection of virus-damaged mammalian lungs. Viruses commonly involved in the predisposition to bacterial pneumonia include influenza A virus (IAV), influenza B virus, respiratory syncytial virus, and human parainfluenza virus (1). Normally, the motility of cilia localized in the tracheal epithelium actively removes mucus, thereby eradicating entrapped foreign particles that would otherwise end up in the lungs. However, when a viral lung infection is already established, the function of the cilia is impaired, paving the way for further invaders (2, 3). Pandemic influenza virus infections such as those of the 2009 H1N1 swine flu pandemic correlated with bacterial superinfections with devastating consequences, such as high morbidity and mortality rates (4-6).Two forms of pneumonia have been distinguished: community-associated pneumonia (CAP) and hospital-associated pneumonia (HAP). In most cases of CAP, Streptococcus pneumoniae has been determined to be the cause of pneumonia (7). Staphylococcus aureus, another aggressive Gram-positive pathogen, causes a variety of diseases in humans, including HAP, especially in ventilated patients (8). CAP is less often caused by S. aureus, except for pneumonia following influenza virus infection, which constitutes a severe secondary infection often resulting in fatal outcomes (9, 10). Moreover, S. aureus iai.asm.org 1 Infection and Immunity causes influenza-associated CAP more frequently in children than in adults (11). Gramnegative bacteria, such as Escherichia coli (12), Haemophilus influenzae (13), Klebsiella ...

No abstract

No abstract