Super-infection withStaphylococcus aureusinhibits influenza virus-induced type I IFN signalling through impaired STAT1-STAT2 dimerization

Abstract

Summary 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.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza

“…It also permits in silico experiments for systems where data is difficult to obtain (e.g., in humans), and aids experimental design to test specific predictions. Carrying out targeted experimental studies based on analytical results, as done previously1850 and here, provides new biological insight about the underlying mechanisms and pinpoints improvements that can be made to our analysis. It is only with these improvements that we will be able to further examine the interactions between influenza, pneumococcus, and the host with new models that assess other immune components.…”

“…However, the cytokine response may be related to the observed viral rebound (Figure S2A), which our model suggests is independent of AM depletion and due to a bacterial induced increase in virus production/release ()17. The increase in virus may be facilitated by the inhibition of IFN50 resulting from bacterial adherence to virus-infected cells155051. With the resulting heightened state of inflammation and severe lung damage, determining how each of these events is interrelated, dose-dependent, and connected to AM depletion is critical to finding new therapeutic approaches.…”

“…Once bacteria invade, virus production/release from infected epithelial cells ( pI 2 ) is increased by a factor of . This term was shown to be the driving mechanism resulting in a viral rebound17 and may result from IFN inhibition as a consequence of bacterial attachment to infected cells1750. The model also assumes that virus infection increases the tissue carrying capacity ( ψV ), which may facilitate bacterial adhesion to cells, and that bacteria increase infected cell death ( μP ).…”

Staphylococcus aureus colonization and non-influenza respiratory viruses: Interactions and synergism mechanisms

“…In addition, influenza virus has been shown to promote S. aureus adhesion and internalization within non-professional phagocytic cells through at least two distinct mechanisms: binding of bacteria to the membrane-associated hemagglutinin of influenza-infected cells, and binding of bacteria to free virions, followed by internalization of virus-coated bacteria into non-infected cells [44]. Besides, S. aureus co-infection promotes influenza virus replication and pathogenicity; indeed, extracellular bacteria secrete staphylokinase that facilitates the binding of influenza virus to the host cells, whereas intracellular S. aureus inhibits influenza virus-induced type I IFN signaling through impaired signal transducers and activators of transcription (STAT1 and STAT2) dimerization [45,46]. While the mechanisms of interaction between S. aureus and influenza virus seem to be deeply understood, the interactions between S. aureus and other respiratory viruses were less investigated.…”

Проблема Бактериальных Осложнений При Респираторных Вирусных Инфекциях

“…Например, известно, что S. aureus может усиливать вирусную репродукцию, негативно воздействуя на передачу сигнала IFN I типа путем препятствова-ния образованию димера STAT-1-STAT-2 [68]. При RSV-инфекции тяжесть заболевания у детей мо-жет определяться превалированием S. pneumoniae и H. influenza в микробиоте перед началом вирусного заболевания [69].…”