The kynurenine pathway contributes to long-term neuropsychological changes in experimental pneumococcal meningitis.
Pneumococcal meningitis is a lethal form of bacterial infection in the central nervous system that often causes lifelong neurological sequelae, despite therapeutic advances. The contemporary view is that the inflammatory response to infection contributes to the functional disabilities among survivors of this disease. We previously have established a mouse model of neurobehavioural deficits, using an automated IntelliCage™ system that revealed long-term behavioural and cognitive deficits in C57BL/6J female mice cured of meningitis by ceftriaxone treatment. We now have investigated the roles of two kynurenine pathway enzymes, indoleamine dioxygenase-1 (IDO1) and tryptophan dioxygenase-2 (TDO2), in the pathomechanisms of pneumococcal meningitis. Since tryptophan metabolism has long been implicated in behavioural and cognitive modulation through the production of neuroactive compounds, we hypothesised that preventing the actions of these enzymes through gene knockout would be beneficial in mice subjected to pneumococcal infection. We found no significant effect of IDO1 or TDO2 on mortality. Post-meningitic wild-type mice showed long-term diurnal hypoactivity and nocturnal hyperactivity when they were exposed to an Intellicage adaptation test throughout both the light and dark phases. These changes were not apparent in IDO1(-/-) survivors, but were present in the TDO2(-/-) survivors. Both IDO1(-/-) and TDO2(-/-) survivors were not protected against developing long-term cognitive deficits as measured in IntelliCage-based patrolling or reversal tasks. Collectively, these observations suggest (i) involvement of the kynurenine pathway in causing some behavioural sequelae of pneumococcal meningitis and (ii) that this pathway might operate synergistically with, or independently of, other pathways to cause other aspects of neurological sequelae.
Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
Lay Khoon
LK
Too
Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
James A
JA
McQuillan
Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
Helen J
HJ
Ball
Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa 078-8510, Japan.
Masaaki
M
Kanai
Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan.
Toshikazu
T
Nakamura
Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa 078-8510, Japan.
Hiroshi
H
Funakoshi
Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa 078-8510, Japan.
Iain S
IS
McGregor
Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address: Nicholas.hunt@sydney.edu.au.
Nicholas H
NH
Hunt
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002443:Ceftriaxone / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency*; D007737:Kynurenine / Q000378:metabolism*; D008586:Meningitis, Pneumococcal / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000523:psychology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009483:Neuropsychological Tests; D014364:Tryptophan / Q000378:metabolism*
D000900:Anti-Bacterial Agents; C583637:IDO1 protein, mouse; C586429:IDO2 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D002443:Ceftriaxone; D014364:Tryptophan
Indoleamine dioxygenase-1; IntelliCage; Kynurenine pathway; Neuroinflammation; Neurological sequelae; Pneumococcal meningitis