ABSTRACT
Bacterial super-infections are a major complication in influenza virus-infected patients. In response to infection with influenza viruses and bacteria, a complex interplay of cellular signalling mechanisms is initiated, regulating the anti-pathogen response but also pathogen-supportive functions. Here, we show that influenza viruses replicate to a higher efficiency in cells co-infected with Staphylococcus aureus (S. aureus). While cells initially respond with increased induction of interferon beta upon super-infection, subsequent interferon signalling and interferon-stimulated gene expression are rather impaired due to a block of STAT1-STAT2 dimerization. Thus, S. aureus interrupts the first line of defence against influenza viruses, resulting in a boost of viral replication, which may lead to enhanced viral pathogenicity.
Subject(s)
Host-Pathogen Interactions , Interferon Type I/metabolism , Orthomyxoviridae/immunology , STAT1 Transcription Factor/metabolism , STAT2 Transcription Factor/metabolism , Staphylococcus aureus/immunology , Virus Replication , Animals , Cell Line , Chlorocebus aethiops , Humans , Orthomyxoviridae/physiology , Protein MultimerizationABSTRACT
The frequent emergence of new influenza viruses in the human population underlines the urgent need for antiviral therapeutics in addition to the preventative vaccination against the seasonal flu. To circumvent the development of resistance, recent antiviral approaches target cellular proteins needed by the virus for efficient replication. We investigated the contribution of the small GTPase Rac1 to the replication of influenza viruses. Inhibition of Rac1 by NSC23766 resulted in impaired replication of a wide variety of influenza viruses, including a human virus strain of the pandemic from 2009 as well as highly pathogenic avian virus strains. Furthermore, we identified a crucial role of Rac1 for the activity of the viral polymerase complex. The antiviral potential of NSC23766 was confirmed in mouse experiments, identifying Rac1 as a new cellular target for therapeutic treatment of influenza virus infections.
Subject(s)
Aminoquinolines/chemistry , Antiviral Agents/chemistry , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae/enzymology , Pyrimidines/chemistry , rac1 GTP-Binding Protein/antagonists & inhibitors , Animals , Apoptosis , Cell Line, Tumor , Dogs , Female , Humans , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred BALB C , RNA-Dependent RNA Polymerase/metabolism , Signal Transduction , Viral Proteins/metabolismABSTRACT
Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton-Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the lung epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.
