Epithelial cells play a crucial role in detection of the pathogens as well as in initiation of the host immune response<i>. Streptococcus pneumoniae</i> (pneumococcus) is a typical colonizer of the human nasopharynx, which can disseminate to the lower respiratory tract and subsequently cause severe invasive diseases such as pneumonia, sepsis, and meningitis. Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) is produced by pneumococci as a product of the pyruvate oxidase SpxB. However, its role as a virulence determinant in pneumococcal infections of the lower respiratory tract is not well understood. In this study, we investigated the role of pneumococcal-derived H<sub>2</sub>O<sub>2</sub> in initiating epithelial cell death by analyzing the interplay between 2 key cell death pathways, namely, apoptosis and pyroptosis. We demonstrate that H<sub>2</sub>O<sub>2</sub> primes as well as activates the NLRP3 inflammasome and thereby mediates IL-1β production and release. Furthermore, we show that pneumococcal H<sub>2</sub>O<sub>2</sub> causes cell death via the activation of both apoptotic as well as pyroptotic pathways which are mediated by the activation of caspase-3/7 and caspase-1, respectively. However, H<sub>2</sub>O<sub>2</sub>-mediated IL-1β release itself occurs mainly via apoptosis.
Influenza A Virus (IAV), <i>Staphylococcus aureus</i> (staphylococci), and <i>Streptococcus pneumoniae</i> (pneumococci) are leading viral and bacterial causes of pneumonia. Dendritic cells (DCs) are present in the lower respiratory tract. They are characterized by low expression of co-stimulatory molecules, including CD80 and CD86 and high capacity of antigen uptake. Subsequently, DCs upregulate co-stimulatory signals and cytokine secretion to effectively induce T-cell priming. Here, we investigated these processes in response to bacterial and viral single as well as coinfections using human monocyte-derived (mo)DCs. Irrespective of single or coinfections, moDCs matured in response to IAV and/or staphylococcal infections, secreted a wide range of cytokines, and activated CD4<sup>+</sup>, CD8<sup>+</sup> as well as double-negative T cells. In contrast, pneumococcal single and coinfections impaired moDC maturation, which was characterized by low expression of CD80 and CD86, downregulated expression of CD40, and a mild cytokine release resulting in abrogated CD4<sup>+</sup> T-cell activation. These actions were attributed to the cholesterol-dependent cytotoxin pneumolysin (Ply). Infections with a <i>ply</i>-deficient mutant resulted in restored moDC maturation and exclusive CD4<sup>+</sup> T-cell activation. These findings show that Ply has important immunomodulatory functions, supporting further investigations in specific modalities of Ply-DC interplay.
The obligate intracellular bacterium Chlamydia trachomatis inserts into the membrane of its vacuole (the inclusion) a family of poorly characterized Inc proteins. While the Inc CpoS was recently revealed as a critical suppressor of host cellular immune surveillance, the underlying mechanism remained unknown. By complementing a cpoS mutant with modified variants of CpoS, we found that CpoS blocks distinct cellular defense responses through distinct mechanisms. Specifically, we show that the ability of CpoS to interact with Rab GTPases is not only instrumental to its ability to mediate lipid transport to the inclusion, but also key to CpoS-mediated inhibition of type I interferon responses. Indeed, depletion of Rab35 can phenocopy the respective defect of the cpoS mutant. Unexpectedly, we found that CpoS is also essential for the formation of inclusion microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. Overall, our findings highlight the modulation of membrane trafficking as a pathogenic immune evasion strategy and the role of Inc-Inc interactions in shaping the inclusion microenvironment.
Community-acquired pneumonia is an infection of the lower respiratory tract caused by various viral and bacterial pathogens, including influenza A virus (IAV), Streptococcus pneumoniae, and Staphylococcus aureus. To understand the disease pathology, it is important to delineate host metabolic responses to an infection. In this study, metabolome profiling of mono-and coinfected human bronchial epithelial cells was performed. We show that IAV and S. aureus silently survive within the cells with almost negligible effects on the host metabolome. In contrast, S. pneumoniae significantly altered various host pathways such as glycolysis, tricarboxylic acid cycle, and amino acid metabolism. Intracellular citrate accumulation was the most prominent signature of pneumococcal infections and was directly attributed to the action of pneumococci-derived hydrogen peroxide. No coinfection specific metabolome signatures were observed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.