Uropathogenic Escherichia coli engages CD14-dependent signaling to enable bladder macrophage-dependent control of acute urinary tract infection

Abstract

INTRODUCTION: CD14, a co-receptor for several pattern recognition receptors and a widely used monocyte/macrophage marker, plays a key role in host responses to Gram-negative bacteria. Despite its central role in the inflammatory response to lipopolysaccharide and other microbial products, and in 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-deficient mice and RNA-sequencing (RNA-seq) to define the CD14-dependent transcriptional signature, and role of CD14, in host defense against UTI in the bladder. RESULTS: UPEC-induced the up-regulation of Cd14 and monocyte/macrophage related genes Emr1/F4/80 and Csf1r/c-fms, which was associated with lower UPEC burdens in WT compared to Cd14-deficient mice. Exacerbation of infection in Cd14-deficient 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 IL-17 signaling. Depletion of monocytes/macrophages in the bladder by administration of liposomal clodronate led to higher UPEC burdens. CONCLUSION: This study identifies new host protective and signaling roles for Cd14 in the bladder during UPEC UTI.