Inhibition of inducible nitric oxide controls pathogen load and brain damage by enhancing phagocytosis of Escherichia coli K1 in neonatal meningitis.
Escherichia coli K1 is a leading cause of neonatal meningitis in humans. In this study, we sought to determine the pathophysiologic relevance of inducible nitric oxide (iNOS) in experimental E. coli K1 meningitis. By using a newborn mouse model of meningitis, we demonstrate that E. coli infection triggered the expression of iNOS in the brains of mice. Additionally, iNOS-/- mice were resistant to E. coli K1 infection, displaying normal brain histology, no bacteremia, no disruption of the blood-brain barrier, and reduced inflammatory response. Treatment with an iNOS specific inhibitor, aminoguanidine (AG), of wild-type animals before infection prevented the development of bacteremia and the occurrence of meningitis. The infected animals treated with AG after the development of bacteremia also completely cleared the pathogen from circulation and prevented brain damage. Histopathological and micro-CT analysis of brains revealed significant damage in E. coli K1-infected mice, which was completely abrogated by AG administration. Peritoneal macrophages and polymorphonuclear leukocytes isolated from iNOS-/- mice or pretreated with AG demonstrated enhanced uptake and killing of the bacteria compared with macrophages and polymorphonuclear leukocytes from wild-type mice in which E. coli K1 survive and multiply. Thus, NO produced by iNOS may be beneficial for E. coli to survive inside the macrophages, and prevention of iNOS could be a therapeutic strategy to treat neonatal E. coli meningitis.
Mittal
Rahul
R
Division of Infectious Diseases, Department of Pathology, MS #51, Childrens Hospital Los Angeles, and the Keck School of Medicine, University of Southern California, 4650 Sunset Blvd, Los Angeles, CA 90027, USA.
Gonzalez-Gomez
Ignacio
I
Goth
Kerstin A
KA
Prasadarao
Nemani V
NV
D000281:Administration, Intranasal; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000166:cytology* / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D008297:Male; D008581:Meningitis / Q000201:enzymology* / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D055114:X-Ray Microtomography
D016207:Cytokines; D006146:Guanidines; D011956:Receptors, Cell Surface; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine