Brain damage in newborn rat model of meningitis by Enterobacter sakazakii: a role for outer membrane protein A.
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.
Mittal
Rahul
R
Department of Pediatrics, Division of Infectious Diseases, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Wang
Ying
Y
Hunter
Catherine J
CJ
Gonzalez-Gomez
Ignacio
I
Prasadarao
Nemani V
NV
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D001769:Blood / Q000382:microbiology; D001770:Blood Bactericidal Activity; D001921:Brain / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D044083:Cronobacter sakazakii / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D020895:Enterocytes / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000473:pathology; D016920:Meningitis, Bacterial / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D009154:Mutation; D020556:Neutrophil Infiltration; D051381:Rats; D017207:Rats, Sprague-Dawley
D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; C078167:OMPA outer membrane proteins