Uropathogenic Escherichia coli Engages CD14-Dependent Signaling to Enable Bladder-Macrophage-Dependent Control of Acute Urinary Tract Infection.
BACKGROUND
CD14, a coreceptor for several pattern recognition receptors and a widely used monocyte/macrophage marker, plays a key role in host responses to gram-negative bacteria. Despite the central role of CD14 in the inflammatory response to lipopolysaccharide and other microbial products and in the dissemination of bacteria in some infections, the signaling networks controlled by CD14 during urinary tract infection (UTI) are unknown.


METHODS
We used uropathogenic Escherichia coli (UPEC) infection of wild-type (WT) C57BL/6 and Cd14(-/-) mice and RNA sequencing to define the CD14-dependent transcriptional signature and the role of CD14 in host defense against UTI in the bladder.


RESULTS
UPEC induced the upregulation of Cd14 and the monocyte/macrophage-related genes Emr1/F4/80 and Csf1r/c-fms, which was associated with lower UPEC burdens in WT mice, compared with Cd14(-/-) mice. Exacerbation of infection in Cd14(-/-) mice was associated with the absence of a 491-gene transcriptional signature in the bladder that encompassed multiple host networks not previously associated with this receptor. CD14-dependent pathways included immune cell trafficking, differential cytokine production in macrophages, and interleukin 17 signaling. Depletion of monocytes/macrophages in the bladder by administration of liposomal clodronate led to higher UPEC burdens.


CONCLUSIONS
This study identifies new host protective and signaling roles for CD14 in the bladder during UPEC UTI.
Menzies Health Institute Queensland, Griffith University, Gold Coast School of Medical Science, Griffith University, Gold Coast.
Alison J
AJ
Carey
Menzies Health Institute Queensland, Griffith University, Gold Coast School of Medical Science, Griffith University, Gold Coast.
Matthew J
MJ
Sullivan
Menzies Health Institute Queensland, Griffith University, Gold Coast School of Medical Science, Griffith University, Gold Coast.
Benjamin L
BL
Duell
Heflin Center for Human Genetics, School of Medicine, University of Alabama at Birmingham.
David K
DK
Crossman
Division of Infectious Diseases, School of Medicine, University of Alabama at Birmingham.
Debasish
D
Chattopadhyay
University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute.
Andrew J
AJ
Brooks
Menzies Health Institute Queensland, Griffith University, Gold Coast School of Medical Science, Griffith University, Gold Coast.
Chee K
CK
Tan
Heflin Center for Human Genetics, School of Medicine, University of Alabama at Birmingham.
Michael
M
Crowley
Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Matthew J
MJ
Sweet
Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
Mark A
MA
Schembri
Menzies Health Institute Queensland, Griffith University, Gold Coast School of Medical Science, Griffith University, Gold Coast Division of Infectious Diseases, School of Medicine, University of Alabama at Birmingham.
Glen C
GC
Ulett
D000818:Animals; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D001743:Urinary Bladder / Q000276:immunology*; D014552:Urinary Tract Infections / Q000276:immunology* / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000276:immunology*
D018950:Lipopolysaccharide Receptors
CD14; RNA sequencing; host response; urinary tract infection; uropathogenic Escherichia coli