Mitogen-activated protein kinases are required for effective infection of human choroid plexus epithelial cells by Listeria monocytogenes.
Listeria monocytogenes, a Gram-positive bacterium, can cause meningitis after invading the human central nervous system. The blood-cerebrospinal fluid barrier (BCSFB), located at the epithelium of the choroid plexus, is a possible entry site for L. monocytogenes into the brain, and in vitro L. monocytogenes invades human choroid plexus epithelial papilloma (HIBCPP) cells. Although host cell signal transduction subsequent to infection by L. monocytogenes has been investigated, the role of mitogen-activated protein kinases (MAPK) is not clarified yet. We show that infection with L. monocytogenes causes activation of the MAPKs Erk1/2 and p38 preferentially when bacteria are added to the physiologically more relevant basolateral side of HIBCPP cells. Deletion of the listerial virulence factors Internalin (InlA) and InlB reduces MAPK activation. Whereas inhibition of either Erk1/2 or p38 signaling significantly attenuates infection of HIBCPP cells with L. monocytogenes, simultaneous inhibition of both MAPK pathways shows an additive effect, and Erk1/2 and p38 are involved in regulation of cytokine and chemokine expression following infection. Blocking of endocytosis with the synthetic dynamin inhibitor dynasore strongly abrogates infection of HIBCPP cells with L. monocytogenes. Concurrent inhibition of MAPK signaling further reduces infection, suggesting MAPKs mediate infection with L. monocytogenes during inhibition of dynamin-mediated endocytosis.
Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Stefanie
S
Dinner
Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Julian
J
Kaltschmidt
Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Carolin
C
Stump-Guthier
Institute of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Svetlana
S
Hetjens
Department of NDU Life Sciences, Nippon Dental University, School of Life Dentistry, Chyoda-ku, Tokyo, Japan.
Hiroshi
H
Ishikawa
Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Tobias
T
Tenenbaum
Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Horst
H
Schroten
Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: christian.schwerk@medma.uni-heidelberg.de.
Christian
C
Schwerk
D002831:Choroid Plexus / Q000382:microbiology*; D004705:Endocytosis; D004847:Epithelial Cells / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*
D020928:Mitogen-Activated Protein Kinases
Blood-cerebrospinal fluid barrier; Choroid plexus; Dynamin; Human; Listeria monocytogenes; Mitogen-activated protein kinase