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The AmiC/NlpD Pathway Dominates Peptidoglycan Breakdown in Neisseria meningitidis and Affects Cell Separation, NOD1 Agonist Production, and Infection

Chan, Jia Mun; Hackett, Kathleen T; Woodhams, Katelynn L; Schaub, Ryan E; Dillard, Joseph P; (2022) The AmiC/NlpD Pathway Dominates Peptidoglycan Breakdown in Neisseria meningitidis and Affects Cell Separation, NOD1 Agonist Production, and Infection. Infection and Immunity , 90 (3) , Article e00485-21. 10.1128/IAI.00485-21. Green open access

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Abstract

The human-restricted pathogen Neisseria meningitidis, which is best known for causing invasive meningococcal disease, has a nonpathogenic lifestyle as an asymptomatic colonizer of the human naso- and oropharyngeal space. N. meningitidis releases small peptidoglycan (PG) fragments during growth. It was demonstrated previously that N. meningitidis releases low levels of tripeptide PG monomer, which is an inflammatory molecule recognized by the human intracellular innate immune receptor NOD1. In this present study, we demonstrated that N. meningitidis released more PG-derived peptides compared to PG monomers. Using a reporter cell line overexpressing human NOD1, we showed that N. meningitidis activates NOD1 using PG-derived peptides. Generation of such peptides required the presence of the periplasmic N-acetylmuramyl-L-alanine amidase AmiC, and the outer membrane lipoprotein, NlpD. AmiC and NlpD were found to function in cell separation, and mutation of either amiC or nlpD resulted in large clumps of unseparated N. meningitidis cells instead of the characteristic diplococci. Using stochastic optical reconstruction microscopy, we demonstrated that FLAG epitope-tagged NlpD localized to the septum, while similarly-tagged AmiC was found at the septum in some diplococci but distributed around the cell in most cases. In a human whole blood infection assay, an nlpD mutant was severely attenuated and showed particular sensitivity to complement. Thus, in N. meningitidis the cell separation proteins AmiC and NlpD are necessary for NOD1 stimulation and for survival during infection of human blood.

Type: Article
Title: The AmiC/NlpD Pathway Dominates Peptidoglycan Breakdown in Neisseria meningitidis and Affects Cell Separation, NOD1 Agonist Production, and Infection
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1128/IAI.00485-21
Publisher version: https://doi.org/10.1128/IAI.00485-21
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: AmiC, NOD1, Neisseria meningitidis, NlpD, amidase, peptidoglycan, peptidoglycan hydrolases, peptidoglycan hydrolysis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10147473
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