Affiliation:
1. Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne, Switzerland
2. Molecular Genetics Group, University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, Centre for Synthetic Biology , Groningen, the Netherlands
3. BioVersys AG , Basel, Switzerland
Abstract
ABSTRACT
Bacteria must adapt to the stresses of specific environmental conditions to survive. This adaptation is often achieved by altering gene expression through two-component regulatory systems (TCSs). In Gram-negative bacteria, the response to environmental changes in osmolarity and pH is primarily mediated by the EnvZ/OmpR TCS. Although the functioning of EnvZ/OmpR has been well characterized in
Escherichia coli
,
Salmonella enterica
, and the
Yersinia
genus, the importance of EnvZ/OmpR TCS in the opportunistic human pathogen
Klebsiella pneumoniae
has been limitedly studied. Here, we investigated the importance of EnvZ/OmpR in
K. pneumoniae
for fitness, gene regulation, virulence, and infection. Through the generation of a markerless
ompR
-deletion mutant, we show that overall fitness of
K. pneumoniae
is not impacted
in vitro
. Using dual RNA sequencing of
K. pneumoniae
co-incubated with human lung epithelial cells, we demonstrate that the
K. pneumoniae
OmpR regulon includes important virulence factors but shows otherwise limited overlap with the regulons of other Gram-negative bacteria. In addition, we show that deletion of
ompR
in
K. pneumoniae
leads to a stronger antibacterial transcriptional response in human lung epithelial cells. Lastly, we show that OmpR is crucial for
K. pneumoniae
virulence and infection through a murine lung infection model. As the adaptation of commensal bacteria to specific niches is mediated by TCSs, we show that EnvZ/OmpR plays a crucial role in successful lung infection, as well as in virulence. These results suggest that OmpR is an interesting target for anti-virulence drug discovery programs.
IMPORTANCE
Bacteria use two-component regulatory systems (TCSs) to adapt to changes in their environment by changing their gene expression. In this study, we show that the EnvZ/OmpR TCS of the clinically relevant opportunistic pathogen
Klebsiella pneumoniae
plays an important role in successfully establishing lung infection and virulence. In addition, we elucidate the
K. pneumoniae
OmpR regulon within the host. This work suggests that
K. pneumoniae
OmpR might be a promising target for innovative anti-infectives.
Funder
Swiss National Science Foundation
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Cell Biology,Microbiology (medical),Genetics,General Immunology and Microbiology,Ecology,Physiology