Affiliation:
1. Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark
Abstract
ABSTRACT
Pseudomonas aeruginosa
airway infections are a major cause of mortality and morbidity of cystic fibrosis (CF) patients. In order to persist,
P. aeruginosa
depends on acquiring iron from its host, and multiple different iron acquisition systems may be active during infection. This includes the pyoverdine siderophore and the
Pseudomonas
heme utilization (
phu
) system. While the regulation and mechanisms of several iron-scavenging systems are well described, it is not clear whether such systems are targets for selection during adaptation of
P. aeruginosa
to the host environment. Here we investigated the within-host evolution of the transmissible
P. aeruginosa
DK2 lineage. We found positive selection for promoter mutations leading to increased expression of the
phu
system. By mimicking conditions of the CF airways
in vitro
, we experimentally demonstrate that increased expression of
phuR
confers a growth advantage in the presence of hemoglobin, thus suggesting that
P. aeruginosa
evolves toward iron acquisition from hemoglobin. To rule out that this adaptive trait is specific to the DK2 lineage, we inspected the genomes of additional
P. aeruginosa
lineages isolated from CF airways and found similar adaptive evolution in two distinct lineages (DK1 and PA clone C). Furthermore, in all three lineages,
phuR
promoter mutations coincided with the loss of pyoverdine production, suggesting that within-host adaptation toward heme utilization is triggered by the loss of pyoverdine production. Targeting heme utilization might therefore be a promising strategy for the treatment of
P. aeruginosa
infections in CF patients.
IMPORTANCE
Most bacterial pathogens depend on scavenging iron within their hosts, which makes the battle for iron between pathogens and hosts a hallmark of infection. Accordingly, the ability of the opportunistic pathogen
Pseudomonas aeruginosa
to cause chronic infections in cystic fibrosis (CF) patients also depends on iron-scavenging systems. While the regulation and mechanisms of several such iron-scavenging systems have been well described, not much is known about how the within-host selection pressures act on the pathogens’ ability to acquire iron. Here, we investigated the within-host evolution of
P. aeruginosa
, and we found evidence that
P. aeruginosa
during long-term infections evolves toward iron acquisition from hemoglobin. This adaptive strategy might be due to a selective loss of other iron-scavenging mechanisms and/or an increase in the availability of hemoglobin at the site of infection. This information is relevant to the design of novel CF therapeutics and the development of models of chronic CF infections.
Publisher
American Society for Microbiology
Cited by
145 articles.
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