RNA-mediated control of virulence genee xpression in Streptococcus pneumoniae

Research output: ThesisPh.D. thesis

Abstract

Streptococcus pneumoniae (pneumococcus) is a major human pathogen and renowned for causing severe infectious diseases such as pneumonia, bacteremia, and meningitis. Globally, it causes nearly 1 million deaths each year, with mortality rates being highest among children under five years of age. Introduction of the pneumococcal conjugate vaccines into national immunization programs in recent decades has successfully reduced child mortality rates. However, due to increased incidences of pneumococcal diseases caused by non-vaccine serotypes, and an increase in antimicrobial resistance (AMR), continuous investigation of pneumococcal virulence mechanisms is important for development of future treatment strategies. Bacterial virulence and host adaptation is regulated by a complex network of regulatory factors controlling the expression of genes important for the survival and fitness of the bacterium at the respective infection site. Regulatory ribonucleic acids (RNAs) have in recent decades been acknowledged as central members of these regulatory circuits in many bacterial pathogens. In pneumococcus, however, their role in virulence and host adaptation remains poorly understood. To fully understand how pneumococcus adapts to the human host environment during an infection, it is essential that this layer to pneumococcal virulence gets elaborated.

To identify regulatory factors involved with pneumococcal virulence, the work of this PhD project explored the transcriptional landscape of pneumococcus involved with host adaptation by different approaches. In Manuscript I, the global transcriptional response of pneumococcus to human blood, and cerebrospinal fluid (CSF) was investigated by RNA-sequencing to identify genes and regulatory factors, including small non-coding RNAs (sRNAs), involved with adaptation to these infection-relevant body fluids. In Manuscript II, we focused on two component-systems (TCSs), which are key bacterial signaling pathways, involved with converting extracellular stimuli into intracellular responses, and often intertwined with RNA regulatory mechanisms. Specifically, we performed a detailed transcriptional and bioinformatic analysis of 11 pneumococcal TCSs to identify novel regulatory target genes, including potential sRNAs. Both transcriptional analyses revealed novel insights into pneumococcal gene regulatory networks, including identification of several sRNAs with potential roles in regulating virulence. In Manuscript III, a more focused approach uncovered a dual function of the messenger RNA (mRNA) encoding the major pneumococcal virulence factor, PspA. In addition to its proteincoding function, it was shown to act as a regulatory RNA element, which via its 3’-untranslated region (3’UTR) controls the expression of the protein chaperone, ClpL. This example emphasizes the increasing diversity of bacterial RNA-mediated regulatory mechanisms being discovered in recent years, as reviewed in Manuscript IV
To identify regulatory factors involved with pneumococcal virulence, the work of this PhD projectexplored the transcriptional landscape of pneumococcus involved with host adaptation by differentapproaches. In Manuscript I, the global transcriptional response of pneumococcus to human blood,and cerebrospinal fluid (CSF) was investigated by RNA-sequencing to identify genes and regulatoryfactors, including small non-coding RNAs (sRNAs), involved with adaptation to these infection-relevantbody fluids. In Manuscript II, we focused on two component-systems (TCSs), which are key bacterialsignaling pathways, involved with converting extracellular stimuli into intracellular responses, and oftenintertwined with RNA regulatory mechanisms. Specifically, we performed a detailed transcriptional andbioinformatic analysis of 11 pneumococcal TCSs to identify novel regulatory target genes, includingpotential sRNAs. Both transcriptional analyses revealed novel insights into pneumococcal generegulatory networks, including identification of several sRNAs with potential roles in regulatingvirulence. In Manuscript III, a more focused approach uncovered a dual function of the messengerRNA (mRNA) encoding the major pneumococcal virulence factor, PspA. In addition to its proteincoding function, it was shown to act as a regulatory RNA element, which via its 3’-untranslated region(3’UTR) controls the expression of the protein chaperone, ClpL. This example emphasizes theincreasing diversity of bacterial RNA-mediated regulatory mechanisms being discovered in recent years,as reviewed in Manuscript IV.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Jørgensen, Mikkel Girke, Principal supervisor
Date of defence11. Aug 2023
Publisher
DOIs
Publication statusPublished - 30. Jun 2023

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