Scaglione, Elena (2020) Role of meningococcal surface-exposed sialic acids in a murine infection model. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: Role of meningococcal surface-exposed sialic acids in a murine infection model
Creators:
CreatorsEmail
Scaglione, Elenaelena.scaglione@unina.it
Date: 11 March 2020
Number of Pages: 89
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricovittorioenrico.avvedimento@unina.it
Tutor:
nomeemail
Salvatore, PaolaUNSPECIFIED
Date: 11 March 2020
Number of Pages: 89
Keywords: Neisseria meningitidis; capsule; meningitis mouse models
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/07 - Microbiologia e microbiologia clinica
Date Deposited: 25 Mar 2020 10:02
Last Modified: 10 Nov 2021 09:58
URI: http://www.fedoa.unina.it/id/eprint/13071

Collection description

Neisseria meningitidis is a leading cause of sepsis and meningitis worldwide in humans. It colonizes the upper respiratory tract of healthy and asymptomatic carriers, but it is able to elude host immune defenses and spreads from the bloodstream to the brain causing uncontrolled local inflammation. Both host and bacterial factors seem to be involved in this switch from harmless transitory colonization to devastating disease. Among its virulence factors, surface-exposed sialic acids occupy a prominent position. In serogroup C N. meningitidis, the cssA gene encodes for an UDP-N-acetylglucosamine 2-epimerase that catalyzes the conversion of UDP-N-acetyl-α-D-glucosamine into N-acetyl-D-mannosamine and UDP in the first step of sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2→9) linked polysialic acid capsule and for lipooligosaccharide sialylation. In this study, was used a reference serogroup C meningococcal strain 93/4286 and an isogenic cssA knockout mutant 93/4286ΩcssA in order to investigate the pathogenetic role of surface-exposed sialic acids in a meningitis model based on intracisternal inoculation of BALB/c mice. The primary results obtained from the 93/4286ΩcssA in vitro characterization, confirmed that the inactivation of cssA gene did not alter the fitness of this mutant and therefore its invasive abilities in a mouse host. Furthermore, the results obtained from the in vivo experiments, confirmed the key role of surface-exposed sialic acids in meningococcal pathogenesis. The LD50 of the wild type strain 93/4286 was about four orders of magnitude lower than that of the cssA mutant. Compared to the wild type strain, the ability of the mutant to replicate in brain and to spread systemically was severely impaired. Evaluation of brain damage evidenced a significant reduction in cerebral haemorrhages in mice infected with the mutant compared to the wild type strain. Histological analysis showed that the experimental murine model reproduces the typical characteristics of bacterial meningitis, particularly in animals infected with the wild type strain. Moreover, the 80% of the mice infected with the reference strain had a massive bacterial localization accompanied by a significant inflammatory infiltrate in the corpus callosum, indicating a high tropism of the meningococci exposing the sialic acids towards this brain structure and its specific involvement in meningococcal meningoencephalitis. This study proposes a new role of microbial surface-exposed sialic acids in the interplay between N. meningitidis and the host in the pathogenesis of meningococcal disease. Meningococcal meningitis still represents an important challenge for human health worldwide. Therefore, this model could be functional for the study of invasive meningococcal disease since N. meningitidis is a strictly human pathogen characterized by a complex infectious cycle and it is considered the paradigm of genetic variation.

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