TY - JOUR
T1 - Evolutionary trade-offs associated with loss of PmrB function in host-adapted Pseudomonas aeruginosa
AU - Bricio-Moreno, Laura
AU - Sheridan, Victoria H.
AU - Goodhead, Ian
AU - Armstrong, Stuart
AU - Wong, Janet K.L.
AU - Waters, Elaine M.
AU - Sarsby, Joscelyn
AU - Panagiotou, Stavros
AU - Dunn, James
AU - Chakraborty, Adrita
AU - Fang, Yongliang
AU - Griswold, Karl E.
AU - Winstanley, Craig
AU - Fothergill, Joanne L.
AU - Kadioglu, Aras
AU - Neill, Daniel R.
N1 - Funding Information:
The study was funded by a British Lung Foundation grant awarded to J.F. and D.N., an Action Medical Research project grant awarded to J.F., D.N., C.W. and A.K. and an MRC project grant awarded to A.K. D.N. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204457/Z/16/Z). J.F. is supported by a Medical Research Foundation Fellowship. K.G. and Y.F. were supported by the National Institutes of Health (Grant Number NIH P20-GM113132). S.A. is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine. We are grateful to the Centre of Proteome Research, supported by the technology directorate, University of Liverpool, and particularly Dr P. Brownridge for instrumentation support. We acknowledge the Manoil lab and NIH grant P30 DK089507 for provision of PAO1 transposon mutants.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018
Y1 - 2018
N2 - Pseudomonas aeruginosa colonises the upper airway of cystic fibrosis (CF) patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We previously experimentally-evolved P. aeruginosa in a murine model of respiratory tract infection and observed early-acquired mutations in pmrB, encoding the sensor kinase of a two-component system that promoted establishment and persistence of infection. Here, using proteomics, we show downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production in pmrB mutants, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type strain LESB65. Accordingly, pmrB mutants are susceptible to antibiotic treatment but show enhanced adherence to airway epithelial cells, resistance to lysozyme treatment, and downregulate host CFTR expression. We propose that P. aeruginosa pmrB mutations in CF patients are subject to an evolutionary trade-off, leading to enhanced colonisation potential, CFTR inhibition, and resistance to host defences, but also to increased susceptibility to antibiotics.
AB - Pseudomonas aeruginosa colonises the upper airway of cystic fibrosis (CF) patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We previously experimentally-evolved P. aeruginosa in a murine model of respiratory tract infection and observed early-acquired mutations in pmrB, encoding the sensor kinase of a two-component system that promoted establishment and persistence of infection. Here, using proteomics, we show downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production in pmrB mutants, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type strain LESB65. Accordingly, pmrB mutants are susceptible to antibiotic treatment but show enhanced adherence to airway epithelial cells, resistance to lysozyme treatment, and downregulate host CFTR expression. We propose that P. aeruginosa pmrB mutations in CF patients are subject to an evolutionary trade-off, leading to enhanced colonisation potential, CFTR inhibition, and resistance to host defences, but also to increased susceptibility to antibiotics.
KW - Bacterial evolution
KW - Bacterial genes
KW - Bacterial host response
KW - Bacterial pathogenesis
UR - http://www.scopus.com/inward/record.url?scp=85049656235&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04996-x
DO - 10.1038/s41467-018-04996-x
M3 - Article
C2 - PMC6035264
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
M1 - 2635
ER -