Abstract
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) induce cystitis, pyelonephritis, and can cause kidney scarring and failure if inflammation is not under control. The detailed effects of cytotoxic necrotizing factor 1 (CNF1), the key UPEC toxin, on the pathogenicity of UPEC remain unclear. CD36 is an important scavenger receptor, responsible for pathogen and apoptotic cell clearance, and plays an essential role in host immune defense and homeostasis. Regulation of CD36 by bacterial toxins has not been reported. In this study, using a pyelonephritis mouse model, CNF1 was observed to contribute to increasing neutrophils and bacterial titers in infected bladder and kidney tissues, resulting in severe inflammation and tissue damage. CD36 expression in macrophages was found to be decreased by CNF1 in vitro and in vivo. We demonstrated that CNF1 attenuated CD36 transcription by decreasing expressions of its upstream transcription factors LXRβ and C/EBPα and their recruitment to the CD36 promotor. In addition, Cdc42 was found to be involved in CNF1-mediated downregulation of LXRβ. Our study investigated the pathogenesis of cnf1-carrying UPEC, which affected host innate immune defenses and homeostasis through regulation of CD36 in macrophages during acute UTIs.
Highlights
Urinary tract infections (UTIs) are one of the commonest bacterial infections, which affect more than 100 million people annually worldwide, and uropathogenic Escherichia coli (UPEC) is the leading cause of UTIs [1,2,3,4]
Infiltrated neutrophils, edema, and urothelial damage were more serious in bladder and kidney tissues infected with UTI89 compared with cnf1 by hematoxylin and eosin (H&E) staining (Figure 2F, Figure S1B)
Macrophages have been reported to be responsible for UPEC phagocytosis in bladder and kidney [36,37,38], and cytotoxic necrotizing factor 1 (CNF1) has been reported to cause apoptosis of bladder cells, possibly leading to bladder cell exfoliation and bacterial access to underlying tissues to interact with macrophages [8, 12, 47]
Summary
Urinary tract infections (UTIs) are one of the commonest bacterial infections, which affect more than 100 million people annually worldwide, and uropathogenic Escherichia coli (UPEC) is the leading cause of UTIs [1,2,3,4]. The innate immune response plays an important role in host defenses during UTIs mediated by UPEC [7]. Phagocytic cells (neutrophils and macrophages) are recruited, and a large panel of cytokines and chemokines are upregulated during the infection to contribute to the innate clearance of UPEC [8,9,10]. Inflammation triggered during innate immunity is necessary. CNF1 Affects CD36 Transcription in Macrophages for bacterial clearance, it should be resolved to prevent severe tissue damage [11]. Unresolved inflammation during UTIs would cause chronic infection and irreversible renal damage [5, 6, 12]
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