title: V-akt murine thymoma viral oncogene homolog 3 (AKT3) contributes to poor disease outcome in humans and mice with pneumococcal meningitis.
abstract: Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Here, we have performed a prospective nationwide genetic association study using the Human Exome BeadChip and identified gene variants in encoding dynactin 4 (DCTN4), retinoic acid early transcript 1E (RAET1E), and V-akt murine thymoma viral oncogene homolog 3 (AKT3) to be associated with unfavourable outcome in patients with pneumococcal meningitis. No clinical replication cohort is available, so we validated the role of one of these targets, AKT3, in a pneumococcal meningitis mouse model. Akt3 deficient mice had worse survival and increased histopathology scores for parenchymal damage (infiltration) and vascular infiltration (large meningeal artery inflammation) but similar bacterial loads, cytokine responses, compared to wild-type mice. We found no differences in cerebrospinal fluid cytokine levels between patients with risk or non-risk alleles. Patients with the risk genotype (rs10157763, AA) presented with low scores on the Glasgow Coma Scale and high rate of epileptic seizures. Thus, our results show that AKT3 influences outcome of pneumococcal meningitis.
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Valls Serón
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands.
authors.forename: JooYeon
authors.initials: J
authors.lastname: Engelen-Lee
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands.
authors.forename: Madelijn
authors.initials: M
authors.lastname: Geldhoff
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands.
authors.forename: Valery
authors.initials: V
authors.lastname: Jaspers
authors.affiliation: Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Medical Microbiology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.|The Netherlands Reference Laboratory for Bacterial Meningitis, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands.
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100DD, Amsterdam, The Netherlands. d.vandebeek@amc.uva.nl.
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016207:Cytokines / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D000072159:Dynactin Complex / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008586:Meningitis, Pneumococcal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009426:Netherlands; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; C000606363:DCTN4 protein, human; D000072159:Dynactin Complex; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C488760:RAET1E protein, human; C491754:AKT3 protein, human; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT3; Bacterial meningitis; Prospective nationwide genetic association study; Streptococcus pneumoniae