ena-STUDY-UTRECHT UNIVERSITY-12-05-2017-11:41:11:708-185
neisseria graft tn-seq
Neisseria meningitidis is the causative agent of cerebrospinal meningitis and that of a rapidly progressing fatal septic shock known as purpura fulminans. Meningococcemia is characterized by bacterial adhesion to human endothelial cells. Host specificity has hampered studies on the role of blood vessels colonization in N. meningitidis associated pathogenesis. In this work, using a humanized model of SCID mice allowing the study of bacterial adhesion to human cells in an in vivo context, we demonstrate that meningococcal colonization of human blood vessels is a prerequisite to the establishment of sepsis and lethality. To understand the molecular pathways involved in virulence, we performed transposon insertion site sequencing (Tn-seq) in vivo. We identified new pathways and showed that graft colonization compensates for the deletion of 36% of the genes important for survival in the blood, suggesting that human endothelial cells lining the blood vessels are feeding niches for N. meningitidis in vivo. All together, our work proposes a new paradigm of meningococcal virulence in which meningococcal colonization of blood vessels is associated with metabolic adaptation and sustained proliferation responsible for sepsis and subsequent lethality.
Neisseria meningitidis is the causative agent of cerebrospinal meningitis and that of a rapidly progressing fatal septic shock known as purpura fulminans. Meningococcemia is characterized by bacterial adhesion to human endothelial cells. Host specificity has hampered studies on the role of blood vessels colonization in N. meningitidis associated pathogenesis. In this work, using a humanized model of SCID mice allowing the study of bacterial adhesion to human cells in an in vivo context, we demonstrate that meningococcal colonization of human blood vessels is a prerequisite to the establishment of sepsis and lethality. To understand the molecular pathways involved in virulence, we performed transposon insertion site sequencing (Tn-seq) in vivo. We identified new pathways and showed that graft colonization compensates for the deletion of 36% of the genes important for survival in the blood, suggesting that human endothelial cells lining the blood vessels are feeding niches for N. meningitidis in vivo. All together, our work proposes a new paradigm of meningococcal virulence in which meningococcal colonization of blood vessels is associated with metabolic adaptation and sustained proliferation responsible for sepsis and subsequent lethality.