RESUMO
Loss of endothelial integrity and vascular leakage are central features of sepsis pathogenesis; however, no effective therapeutic mechanisms for preserving endothelial integrity are available. Here we show that, compared to dermal microvessels, brain microvessels resist infection by Neisseria meningitidis, a bacterial pathogen that causes sepsis and meningitis. By comparing the transcriptional responses to infection in dermal and brain endothelial cells, we identified angiopoietin-like 4 as a key factor produced by the brain endothelium that preserves blood-brain barrier integrity during bacterial sepsis. Conversely, angiopoietin-like 4 is produced at lower levels in the peripheral endothelium. Treatment with recombinant angiopoietin-like 4 reduced vascular leakage, organ failure and death in mouse models of lethal sepsis and N. meningitidis infection. Protection was conferred by a previously uncharacterized domain of angiopoietin-like 4, through binding to the heparan proteoglycan, syndecan-4. These findings reveal a potential strategy to prevent endothelial dysfunction and improve outcomes in patients with sepsis.
Assuntos
Modelos Animais de Doenças , Células Endoteliais , Sepse , Animais , Sepse/microbiologia , Camundongos , Humanos , Células Endoteliais/metabolismo , Células Endoteliais/microbiologia , Neisseria meningitidis/genética , Neisseria meningitidis/metabolismo , Proteína 4 Semelhante a Angiopoietina/metabolismo , Proteína 4 Semelhante a Angiopoietina/genética , Barreira Hematoencefálica/metabolismo , Infecções Meningocócicas/microbiologia , Encéfalo/metabolismo , Encéfalo/microbiologia , Encéfalo/patologia , Camundongos Endogâmicos C57BL , Endotélio Vascular/metabolismo , Endotélio Vascular/microbiologiaRESUMO
Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of the illness at the dawn of the nineteenth century, the scientific knowledge of meningococcal infection has increased greatly. Major advances have been made in the management of the disease with the advent of antimicrobial therapy and the implementation of meningococcal vaccines. More recently, an extensive knowledge has been accumulated on meningococcal interaction with its human host, revealing key processes involved in disease progression and new promising therapeutic approaches.
Neisseria meningitidis (méningocoque) est une bactérie à Gram négatif responsable de deux formes gravissimes de maladies invasives : le purpura fulminans et la méningite. Depuis la première description du caractère épidémique de la maladie à l'aube du 19e siècle, les connaissances scientifiques sur les infections méningococciques ont considérablement augmenté. Des progrès majeurs ont été réalisés dans la gestion de la maladie avec l'avènement des agents antimicrobiens et le développement de vaccins contre le méningocoque. De nombreuses connaissances ont récemment été accumulées sur son interaction avec l'être humain, son unique hôte, révélant les processus clés impliqués dans la progression de la maladie et de nouvelles approches thérapeutiques prometteuses.
Assuntos
Infecções Meningocócicas , Neisseria meningitidis , Púrpura Fulminante , Antibacterianos , Humanos , Infecções Meningocócicas/tratamento farmacológico , Púrpura Fulminante/tratamento farmacológicoRESUMO
Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Interaction with both peripheral and cerebral microvascular endothelial cells is at the heart of meningococcal pathogenesis. During the last two decades, an essential role for meningococcal type IV pili in vascular colonisation and disease progression has been unravelled. This review summarises 20 years of research on meningococcal type IV pilus-dependent virulence mechanisms, up to the identification of promising anti-virulence compounds that target type IV pili.
