Cicatiello, Annunziata Gaetana (2016) Characterization of Neisseria meningitidis rifampicin resistant strains: highlight on molecular mechanisms underlying the phenotypic traits associated with the RpoB H553Y substitution. [Tesi di dottorato]
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | Characterization of Neisseria meningitidis rifampicin resistant strains: highlight on molecular mechanisms underlying the phenotypic traits associated with the RpoB H553Y substitution |
| Creators: | Creators Email Cicatiello, Annunziata Gaetana annunziatagaetana.cicatiello2@unina.it |
| Date: | 2016 |
| Number of Pages: | 120 |
| Institution: | Università degli Studi di Napoli Federico II |
| Department: | Medicina Molecolare e Biotecnologie Mediche |
| Scuola di dottorato: | Medicina molecolare |
| Dottorato: | Patologia e fisiopatologia molecolare |
| Ciclo di dottorato: | 28 |
| Coordinatore del Corso di dottorato: | nome email Avvedimento, Vittorio Enrico vittorioenrico.avvedimento@unina.it |
| Tutor: | nome email Salvatore, Paola UNSPECIFIED |
| Date: | 2016 |
| Number of Pages: | 120 |
| Keywords: | rifampicin; resistance; Neisseria meningitidis |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/07 - Microbiologia e microbiologia clinica |
| Date Deposited: | 13 Apr 2016 10:42 |
| Last Modified: | 21 Nov 2016 11:03 |
| URI: | http://www.fedoa.unina.it/id/eprint/10869 |
Collection description
Rifampicin chemoprophylaxis against Neisseria meningitidis infections led to the onset of rifampicin resistance in clinical isolates harboring point mutations in the rpoB gene, coding for the RNA polymerase β chain. These resistant strains are rare in medical practice, suggesting their decreased fitness in the human host. In this study, we isolated rifampicin-resistant rpoB mutants from hypervirulent serogroup C strain 93/4286 and analyzed their different properties, including the ability to grow and survive in different culture media and in differentiated THP-1 human monocytes and to compete with the wild-type strain in vitro. Our results demonstrate that different rpoB mutations (H553Y, H553R and S549F) may have different effects, ranging from low- to high-cost, on bacterial fitness in vitro. Moreover, we found that the S549F mutation confers temperature sensitivity, possibly explaining why it is observed very rarely in clinical isolates. Comparative high-throughput RNA sequencing analysis of bacteria grown in chemically defined medium demonstrated that the low-cost H553Y substitution resulted in global transcriptional changes that functionally mimic the stringent response. Interestingly, many virulence-associated genes, including those coding for meningococcal type IV pili, porin A, adhesins/invasins, IgA protease, two-partner secretion system HrpA/HrpB, enzymes involved in resistance to oxidative injury, lipooligosaccharide sialylation, and capsular polysaccharide biosynthesis, were down regulated in the H553Y mutant compared to their level of regulation in the wild-type strain. These data might account for the reduced capacity of H553Y mutant to grow and survive in differentiated THP-1 cells and explain the rarity of this mutant in clinical isolates.
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