Globale Expressionsprofile Pneumokokken-infizierter Bronchialepithelzellen - Einfluss der miRNA-3135b und des Nicotinamidstoffwechselweges auf die bakterielle Replikation
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Philipps-Universität Marburg
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Abstract
Streptococcus pneumoniae, the pneumococcus, is a gram‐positive bacterium that colonizes the
human nasopharynx as a commensal, in most cases asymptomatically, but can also cause
severe diseases, including sepsis or meningitis. Pneumococci are major pathogens of human
pneumonia, causing millions of death each year worldwide. Furthermore, co‐infections with
Influenza A viruses can worsen the disease. Increasing abundance of antibiotics resistance
makes treatment more and more difficult. The epithelial cells of the human respiratory tract
are the first line of defense against the infection. However, many aspects of the interaction
between epithelial cells and S. pneumoniae have not been fully elucidated yet.
To analyze this interaction in detail, an expression profile of mRNAs, proteins and miRNAs of
infected bronchial epithelial cells has been created. In addition, a co‐infection model in human
ex vivo lung tissue was investigated for comparison. Pathway analysis of the infected epithelial
cells revealed an up‐regulation of cell cycle associated molecules at 16 h post infection. Linking
of the data with the miRNA profile revealed mainly known interaction partners.
However, treatment‐dependent expression patterns of miRNAs have been detected, which
revealed miRNAs specifically induced by S. pneumoniae, but not isolated TLR2‐ligation, such as
miRNA‐3135b. Overexpression of miRNA‐3135b resulted in a significant reduction in
pneumococcal load, suggesting involvement of a defense mechanism of epithelial cells. In
addition, RNA sequencing after miRNA‐3135b overexpression revealed various putative target
mRNAs, whose functions are currently only partially known. It is currently still under
investigation if miRNA‐3135b is a bona fide miRNA or a t‐RNA‐derived fragment (tRF).
Furthermore, functional analyses of regulated mRNAs and proteins indicated involvement of
the nicotinamide metabolism. In epithelial cells, depletion of NAMPT, the key enzyme of this
pathway, resulted in a reduced replication of S. pneumoniae. Moreover, the addition of
nicotinamide mononucleotide (NMN) caused an increased rate of bacterial replication. This
suggests NMN might be an important nutrient source of pneumococci.
The data from this work extends the understanding of the interaction of human epithelial cells
and pneumococci, and might be useful for the identification of alternative or adjuvant
therapeutic strategies.
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Dates
Created: 2018Issued: 2019-04-23Updated: 2019-04-23
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
infectionpneumococcinicotinamideStreptococcus pneumoniaepneumoniapathogen-host interactionmicroRNAs
DFG-subjects
Pathogen-Wirts-InteraktionmicroRNAsPneumokokkenStreptococcus pneumoniaeNicotinamidInfektionPneumonie
DDC-Numbers
610
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Wesener, André: Globale Expressionsprofile Pneumokokken-infizierter Bronchialepithelzellen - Einfluss der miRNA-3135b und des Nicotinamidstoffwechselweges auf die bakterielle Replikation. : Philipps-Universität Marburg 2019-04-23. DOI: https://doi.org/10.17192/z2018.0345.
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This item has been published with the following license: In Copyright