Late Repression of NF-κB Activity by Invasive but Not Non-Invasive Meningococcal Isolates Is Required to Display Apoptosis of Epithelial Cells

Ala-Eddine Deghmane,Aziza Abaza,Dario Giorgini,Hela El Kafsi,Muhamed-Kheir Taha,Craig R Roy

doi:10.1371/journal.ppat.1002403

Abstract

Meningococcal invasive isolates of the ST-11 clonal complex are most frequently associated with disease and rarely found in carriers. Unlike carriage isolates, invasive isolates induce apoptosis in epithelial cells through the TNF-α signaling pathway. While invasive and non-invasive isolates are both able to trigger the TLR4/MyD88 pathway in lipooligosaccharide (LOS)-dependant manner, we show that only non-invasive isolates were able to induce sustained NF-κB activity in infected epithelial cells. ST-11 invasive isolates initially triggered a strong NF-κB activity in infected epithelial cells that was abolished after 9h of infection and was associated with sustained activation of JNK, increased levels of membrane TNFR1, and induction of apoptosis. In contrast, infection with carriage isolates lead to prolonged activation of NF-κB that was associated with a transient activation of JNK increased TACE/ADAM17-mediated shedding of TNFR1 and protection against apoptosis. Our data provide insights to understand the meningococcal duality between invasiveness and asymptomatic carriage.

Highlights

The exclusive human bacterium Neisseria meningitidis is a major cause of infectious diseases worldwide, including meningitis and fulminant sepsis that are associated with significant morbidity and case fatality rates ranging from 10 to 50% in patients with severe septicaemia [1,2] and up to 20% of survivors sustain neurological sequelae [3]
Strains of Neisseria meningitidis isolated from patients induce apoptotic cell death through the tumor necrosis factor alpha (TNF-a) pathway, whereas strains isolated from healthy carriage isolates do not
Part of the difference has been shown to arise from differential shedding of the type 1 TNF-a receptor (TNFR1) from the surface of the cells infected with the carriage isolates

Summary

Introduction

The exclusive human bacterium Neisseria meningitidis (the meningococcus) is a major cause of infectious diseases worldwide, including meningitis and fulminant sepsis that are associated with significant morbidity and case fatality rates ranging from 10 to 50% in patients with severe septicaemia [1,2] and up to 20% of survivors sustain neurological sequelae [3]. Despite this notoriety, N. meningitidis is a frequent inhabitant of the nasopharyngeal mucosa being asymptomatically carried by 10–35% of the adult population [4,5]. A better understanding of the pathogenesis of this disease, notably the interaction with host cells, is central in developing new anti-meningococcal strategies

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