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Int J Mol Sci ; 22(8)2021 Apr 08.
Article in English | MEDLINE | ID: covidwho-1299441


Pneumonia due to respiratory infection with most prominently bacteria, but also viruses, fungi, or parasites is the leading cause of death worldwide among all infectious disease in both adults and infants. The introduction of modern antibiotic treatment regimens and vaccine strategies has helped to lower the burden of bacterial pneumonia, yet due to the unavailability or refusal of vaccines and antimicrobials in parts of the global population, the rise of multidrug resistant pathogens, and high fatality rates even in patients treated with appropriate antibiotics pneumonia remains a global threat. As such, a better understanding of pathogen virulence on the one, and the development of innovative vaccine strategies on the other hand are once again in dire need in the perennial fight of men against microbes. Recent data show that the secretome of bacteria consists not only of soluble mediators of virulence but also to a significant proportion of extracellular vesicles-lipid bilayer-delimited particles that form integral mediators of intercellular communication. Extracellular vesicles are released from cells of all kinds of organisms, including both Gram-negative and Gram-positive bacteria in which case they are commonly termed outer membrane vesicles (OMVs) and membrane vesicles (MVs), respectively. (O)MVs can trigger inflammatory responses to specific pathogens including S. pneumonia, P. aeruginosa, and L. pneumophila and as such, mediate bacterial virulence in pneumonia by challenging the host respiratory epithelium and cellular and humoral immunity. In parallel, however, (O)MVs have recently emerged as auspicious vaccine candidates due to their natural antigenicity and favorable biochemical properties. First studies highlight the efficacy of such vaccines in animal models exposed to (O)MVs from B. pertussis, S. pneumoniae, A. baumannii, and K. pneumoniae. An advanced and balanced recognition of both the detrimental effects of (O)MVs and their immunogenic potential could pave the way to novel treatment strategies in pneumonia and effective preventive approaches.

Bacteria/metabolism , Bacterial Outer Membrane/metabolism , Extracellular Vesicles/metabolism , Pneumonia, Bacterial/microbiology , Adaptive Immunity , Animals , Antigens, Bacterial/immunology , Bacteria/immunology , Bacterial Outer Membrane/immunology , Bacterial Vaccines/immunology , Host-Pathogen Interactions/immunology , Humans , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/prevention & control , Respiratory Mucosa/immunology , Respiratory Mucosa/microbiology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/prevention & control , Virulence
The FASEB Journal ; 35(S1), 2021.
Article in English | Wiley | ID: covidwho-1233934


Study objective Endothelial dysfunction and increased microvascular permeability are hallmarks of severe COVID-19. At present, the extent of endothelial barrier failure and its underlying mechanisms in COVID?19 remain unclear. We hypothesized that endothelial leak results from bioactive mediators released in COVID-19 rather than direct endothelial infection and can thus be recapitulated ex vivo by treating endothelial cells with patient plasma, thus providing a personalized screening platform for barrier-protective interventions in COVID-19. Methods Citrate plasma was sampled as part of the Pa-COVID-19 cohort study (ethics approval EA2/066/20) in patients with moderate (hospitalized, no invasive ventilation;WHO severity score: 3-4) and severe (high flow O2 or intubated and mechanically ventilated;WHO severity score: 5-7) COVID?19. Plasma samples were diluted to 10% (v/v) in cell culture medium without FCS and tested for their ability to disrupt barrier integrity of primary human pulmonary microvascular endothelial cells (HPMEC) monolayers by electrical cell-substrate impedance sensing (ECIS), immunofluorescence for endothelial VE-cadherin and F-actin, and real-time Ca2+ imaging. Plasma from healthy donors served as control. Results COVID-19 plasma was virus-free but caused endothelial barrier disruption as measured by ECIS and gap formation in HPMEC monolayers. The extent of barrier disruption increased with disease severity but varied considerably between endothelial cells from different microvascular beds (lung/heart >> skin). The TRPV4-antagonist HC-067047 prevented the endothelial Ca2+ response to COVID-19 plasma and protected endothelial barrier integrity in lung microvascular cells. Conclusion Here, we identify TRPV4 as critical regulator of microvascular permeability in COVID?19. Targeting TRPV4-mediated endothelial barrier failure may present a promising adjunctive therapy in COVID-19.