TY - JOUR
T1 - Brain damage in newborn rat model of meningitis by Enterobacter sakazakii
T2 - A role for outer membrane protein A
AU - Mittal, Rahul
AU - Wang, Ying
AU - Hunter, Catherine J.
AU - Gonzalez-Gomez, Ignacio
AU - Prasadarao, Nemani V.
N1 - Funding Information:
We thank Barbara Driscoll for a critical reading of the paper. We also thank Fred Dorey for help in statistical analysis. This study was supported by NIH grant AI40567.
PY - 2009/3
Y1 - 2009/3
N2 - Enterobacter sakazakii (ES) is an emerging pathogen that causes sepsis, meningitis, and necrotizing enterocolitis in neonates. Very limited information is available regarding the pathogenesis of these diseases and the specific virulence factors of ES. Here, we demonstrate, for the first time using a newborn rat model, that outer membrane protein A (OmpA) expression is important for the onset of meningitis by ES. Orally administered OmpA+ ES traverses the intestinal barrier, multiplies in blood, and subsequently penetrates the blood-brain barrier. OmpA+ ES were present in high numbers in the brains of infected animals along with associated neutrophil infiltration, hemorrhage, and gliosis. In contrast, OmpA- ES could not bind to the intestinal epithelial cells in vitro and in vivo efficiently. The bound OmpA+ ES also caused apoptosis of enterocytes in the intestinal segments of infected animals; OmpA- ES did not. Furthermore, OmpA- ES are very susceptible to blood and serum killing, whereas OmpA+ ES are resistant. Of note, 100% mortality rates were observed in OmpA+ ES-infected newborn rats, whereas OmpA- ES-infected rats survived without any pathological manifestations. The inability of OmpA- ES to cause disease was restored by complementation with the ompA gene. These results suggest that OmpA expression in ES is necessary for the colonization of the gastrointestinal tract and for subsequent survival in blood to cause meningitis.
AB - Enterobacter sakazakii (ES) is an emerging pathogen that causes sepsis, meningitis, and necrotizing enterocolitis in neonates. Very limited information is available regarding the pathogenesis of these diseases and the specific virulence factors of ES. Here, we demonstrate, for the first time using a newborn rat model, that outer membrane protein A (OmpA) expression is important for the onset of meningitis by ES. Orally administered OmpA+ ES traverses the intestinal barrier, multiplies in blood, and subsequently penetrates the blood-brain barrier. OmpA+ ES were present in high numbers in the brains of infected animals along with associated neutrophil infiltration, hemorrhage, and gliosis. In contrast, OmpA- ES could not bind to the intestinal epithelial cells in vitro and in vivo efficiently. The bound OmpA+ ES also caused apoptosis of enterocytes in the intestinal segments of infected animals; OmpA- ES did not. Furthermore, OmpA- ES are very susceptible to blood and serum killing, whereas OmpA+ ES are resistant. Of note, 100% mortality rates were observed in OmpA+ ES-infected newborn rats, whereas OmpA- ES-infected rats survived without any pathological manifestations. The inability of OmpA- ES to cause disease was restored by complementation with the ompA gene. These results suggest that OmpA expression in ES is necessary for the colonization of the gastrointestinal tract and for subsequent survival in blood to cause meningitis.
KW - Enterobacter sakazakii
KW - Meningitis
KW - Outer membrane protein A
KW - Rat brain
KW - Survival
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U2 - 10.1038/labinvest.2008.164
DO - 10.1038/labinvest.2008.164
M3 - Article
C2 - 19139724
AN - SCOPUS:61349123502
VL - 89
SP - 263
EP - 277
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 3
ER -