Abstract
Pneumonia is the leading cause of hospitalization worldwide. Besides viruses, bacterial co-infections dramatically exacerbate infection. In general, surfactant protein-A (SP-A) represents a first line of immune defense. In this study, we analyzed whether influenza A virus (IAV) and/or Staphylococcus aureus (S. aureus) infections affect SP-A expression. To closely reflect the situation in the lung, we used a human alveolus-on-a-chip model and a murine pneumonia model. Our results show that S. aureus can reduce extracellular levels of SP-A, most likely attributed to bacterial proteases. Mono-epithelial cell culture experiments reveal that the expression of SP-A is not directly affected by IAV or S. aureus. Yet, the mRNA expression of SP-A is strongly down-regulated by TNF-α, which is highly produced by professional phagocytes in response to bacterial infection. By using the human alveolus-on-a-chip model, we show that the down-regulation of SP-A is strongly dependent on macrophages. In a murine model of pneumonia, we can confirm that S. aureus decreases SP-A levels in vivo. These findings indicate that (I) complex interactions of epithelial and immune cells induce down-regulation of SP-A expression and (II) bacterial mono- and super-infections reduce SP-A expression in the lung, which might contribute to a severe outcome of bacterial pneumonia.
Highlights
Pneumonia is the most severe inflammatory disease of the lower respiratory tract and the most common infectious disease worldwide
Our results show that beside the direct effect of S. aureus leading to the cleavage of extracellular surfactant protein-A (SP-A), there is an indirect effect based on infection via the cytokine production, notably by TNF-α
Pneumonia is the leading cause of morbidity and mortality worldwide and viral/bacterial co-infection worsens the severity of the disease
Summary
Pneumonia is the most severe inflammatory disease of the lower respiratory tract and the most common infectious disease worldwide. Influenza A and B viruses (IAV, IBV) are primary causative agents [1]. S. aureus colonizes epithelial surfaces, but can cause a broad spectrum of infections ranging from superficial skin infections to life-threatening diseases, such as bacterial pneumonia [2]. The first line of defense during infections, apart from physical barriers, is regulated by an innate host immune response in which white blood cells and chemical components play a crucial role [3]. The non-specific cellular response, including mucous and surfactant proteins, are principal targets to fight pathogens [5]. Surfactant proteins have immunomodulatory and antimicrobial activity and thereby are important agents in primary host immune defense [6,7,8]
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