Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent.

Berhane Asfaw Idosa,Anne Kelly,Eva Särndahl,Alexander Persson,Isak Demirel,Susanne Jacobsson,Hans Fredlund

doi:10.1155/2019/6193186

Berhane Asfaw Idosa, Anne Kelly + Show 5 more

Open Access

https://doi.org/10.1155/2019/6193186

Copy DOI

Abstract

Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1β (IL-1β), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanism—priming and licensing of inflammasome activation—but there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1β release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.

Highlights

Meningococci are considered commensals in the nasopharyngeal mucosa, and it is estimated that 10-40% of the general population are asymptomatic carriers, providing the reservoir for this obligate human pathogen [1, 2]
The aim of the current study was to investigate if N. meningitidis mediates inflammasome activation and, if so, what role the meningococcal virulence factor LOS plays in this process
Since the activated inflammasome recruits procaspase-1 and triggers its activation, the level of cleaved caspase-1 was analyzed as a marker of inflammasome activation [25, 29], both in neutrophils and in monocytes in whole blood as well as in isolated neutrophils

Summary

Introduction

Meningococci are considered commensals in the nasopharyngeal mucosa, and it is estimated that 10-40% of the general population are asymptomatic carriers, providing the reservoir for this obligate human pathogen [1, 2]. The interconnection between asymptomatic carriage and disease development is not known. Neisseria meningitidis is the major causative agent of sepsis and bacterial meningitis globally [3] with the highest incidence of meningococcal disease occurring in the meningitis belt of sub-Saharan Africa that extends across the regions from Senegal in the west to Ethiopia in the east [3, 4]. Severity of meningococcal disease varies among individuals, in whom some suffer from meningitis alone, while others may develop meningococcemia with mild or severe sepsis [6, 7]. It is generally believed that the bacterial virulence factors in combination with the individual’s unique immune system determine

Objectives

Methods

Results

Conclusion