CD46 (Membrane Cofactor Protein) Acts as a Human Epithelial Cell Receptor for Internalization of Opsonized Uropathogenic Escherichia coli

Abstract

Escherichia coli is a common urinary pathogen whose uptake into epithelial cells is mediated by attachment through type 1 fimbriae. In this study, we show by using using human urinary tract epithelial cells that maximal internalization of E. coli is achieved only when bacteria are opsonized with complement. The concentrations of complement proteins in the urine rise sufficiently during infection to allow bacterial opsonization. The complement regulatory protein, CD46 (membrane cofactor protein), acts in cohort with fimbrial adhesion to promote the uptake of pathogenic E. coli. This uptake is inhibited by RNA interference to lower the expression of CD46 and by soluble CD46 that will competitively inhibit opsonized bacteria binding to cell surface CD46. We propose that efficient internalization of uropathogenic E. coli by the human urinary tract depends on cooperation between fimbrial-mediated adhesion and C3 receptor (CD46)–ligand interaction. Complement receptor–ligand interaction could pose a new target for interrupting the cycle of reinfection due to intracellular bacteria.

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

“…In the murine system, chemokine activation requires both CD46 expression on the surface and signaling through TLR9, which suggests that CD46 mediates the capture and internalization of HHV-6A viral particles, allowing access of viral DNA to the endosomal compartment containing TLR9. Indeed, CD46 was shown to efficiently internalize opsonized bacteria (77) and to transport measles virus into the endosome/lysosome compartment for efficient major histocompatibility complex class II-restricted presentation in both human (78) and murine cells (79). Furthermore, our results demonstrate that in addition to the murine TLR9, HHV-6A could stimulate human TLR9, underlining the significance of the murine model for studying this aspect of HHV-6A pathogenesis.…”

Macropinocytotic Uptake and Infection of Human Epithelial Cells with Species B2 Adenovirus Type 35

“…In addition to binding to the species B HAdVs, CD46 also binds the Edmonston strain of measles virus (22,74), human herpes virus 6 (88), bovine viral diarrhea virus (61), and various bacteria, including uropathogenic Escherichia coli (54,56). The selection of CD46 as a receptor for numerous pathogens suggests that there are advantages for pathogens in binding to CD46, e.g., dampening or suppression of innate immune responses (43,76).…”

The Cpx Stress Response System Potentiates the Fitness and Virulence of Uropathogenic Escherichia coli

“…Urine, like serum, contains numerous antibacterial factors, including heat-labile components of the complement system that can mediate bacterial opsonization and the formation of membrane attack complexes (14,(83)(84)(85). By modulating the composition and resilience of the bacterial envelope, we hypothesized that the Cpx system can alter the sensitivity of UPEC to serum components.…”

“…Prior to introduction into the urinary tract, UPEC likely first colonizes the host nasopharynx and gastrointestinal tract, where it does not appear to elicit any overt pathology (7)(8)(9). Within these varied host environments, and while in transit between hosts, UPEC will encounter an assorted array of stresses, including reactive nitrogen and oxygen species, nutrient limitation, shearing forces, professional phagocytes, complement and other antimicrobial compounds, competition with other microbes and, potentially, antibiotics (10)(11)(12)(13)(14)(15). The ability to deal with these stresses is of paramount importance to the success of UPEC as a pathogen.…”