title: Escherichia coli K1 induces pterin production for enhanced expression of Fcγ receptor I to invade RAW 264.7 macrophages.
abstract: Macrophages serve as permissive niches for Escherichia coli (E. coli) K1 to attain high grade bacteremia in the pathogenesis of meningitis in neonates. Although pterin levels are a diagnostic marker for immune activation, the role of macrophages in pterin production and in the establishment of meningitis is unknown. Here, we demonstrate that macrophages infected with E. coli K1 produce both neopterin and biopterin through increased expression of GTP-cyclohydrolase 1 (GCH1). Of note, increased production of biopterin enhances the expression of Fc-gamma receptor I (CD64), which in turn, aided the entry of E. coli K1 in macrophages while increased neopterin suppresses reactive oxygen species (ROS), thereby aiding bacterial survival. Inhibition of GCH1 by 2, 4-Diamino-6-hydroxypyrimidine (DAHP) prevented the E. coli K1 induced expression of CD64 in macrophages in vitro and the development of bacteremia in a newborn mouse model of meningitis. These studies suggest that targeting GCH1 could be therapeutic strategy for preventing neonatal meningitis by E. coli K1.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
authors.forename: Muthusamy V
authors.initials: MV
authors.lastname: Shanmuganathan
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Fu
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA; Department of Surgery, Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd., Los Angeles, CA 90027, USA. Electronic address: pnemani@chla.usc.edu.
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016470:Bacteremia / Q000382:microbiology / Q000473:pathology; D002460:Cell Line; D004705:Endocytosis; D004926:Escherichia coli / Q000502:physiology*; D005260:Female; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000382:microbiology*; D016920:Meningitis, Bacterial / Q000150:complications / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011622:Pterins / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*
chemical_list: D011622:Pterins; D017452:Receptors, IgG; D006136:GTP Cyclohydrolase
keywords: Biopterin; E. coli K1; Macrophages; Meningitis; Neopterin