title: Listeria monocytogenes spreads within the brain by actin-based intra-axonal migration.
abstract: Listeria monocytogenes rhombencephalitis is a severe progressive disease despite a swift intrathecal immune response. Based on previous observations, we hypothesized that the disease progresses by intra-axonal spread within the central nervous system. To test this hypothesis, neuroanatomical mapping of lesions, immunofluorescence analysis, and electron microscopy were performed on brains of ruminants with naturally occurring rhombencephalitis. In addition, infection assays were performed in bovine brain cell cultures. Mapping of lesions revealed a consistent pattern with a preferential affection of certain nuclear areas and white matter tracts, indicating that Listeria monocytogenes spreads intra-axonally within the brain along interneuronal connections. These results were supported by immunofluorescence and ultrastructural data localizing Listeria monocytogenes inside axons and dendrites associated with networks of fibrillary structures consistent with actin tails. In vitro infection assays confirmed that bacteria were moving within axon-like processes by employing their actin tail machinery. Remarkably, in vivo, neutrophils invaded the axonal space and the axon itself, apparently by moving between split myelin lamellae of intact myelin sheaths. This intra-axonal invasion of neutrophils was associated with various stages of axonal degeneration and bacterial phagocytosis. Paradoxically, the ensuing adaxonal microabscesses appeared to provide new bacterial replication sites, thus supporting further bacterial spread. In conclusion, intra-axonal bacterial migration and possibly also the innate immune response play an important role in the intracerebral spread of the agent and hence the progression of listeric rhombencephalitis.
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Henke
authors.affiliation: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rupp
authors.affiliation: Division of Veterinary Anatomy, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gaschen
authors.affiliation: Division of Veterinary Anatomy, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Stoffel
authors.affiliation: Institute of Veterinary Bacteriology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Frey
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Vandevelde
authors.affiliation: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland anna.oevermann@vetsuisse.unibe.ch.
authors.forename: Anna
authors.initials: A
authors.lastname: Oevermann
mesh_terms: D000818:Animals; D001369:Axons; D001921:Brain / Q000166:cytology / Q000382:microbiology*; D002417:Cattle; D002418:Cattle Diseases / Q000382:microbiology* / Q000473:pathology; D004660:Encephalitis / Q000382:microbiology / Q000473:pathology / Q000662:veterinary*; D015511:Goat Diseases / Q000382:microbiology* / Q000473:pathology; D006041:Goats; D008089:Listeria monocytogenes / Q000502:physiology*; D008088:Listeriosis / Q000382:microbiology*; D009068:Movement; D012756:Sheep; D012757:Sheep Diseases / Q000382:microbiology* / Q000473:pathology
references.citation: Med Microbiol Immunol. 1999 Aug;188(1):15-21
references.pmid: 10691089
references.citation: Brain Pathol. 2010 Mar;20(2):378-90
references.pmid: 19476464
references.citation: Curr Top Microbiol Immunol. 2005;292:45-56
references.pmid: 15981467
references.citation: J Pathol. 2015 Jan;235(2):277-87
references.pmid: 25294743
references.citation: Nat Rev Neurosci. 2011 Jun;12(6):345-57
references.pmid: 21587289
references.citation: Int J Exp Pathol. 2012 Aug;93(4):259-68
references.pmid: 22804762
references.citation: Brain Pathol. 2001 Oct;11(4):432-8
references.pmid: 11556688
references.citation: Med Mal Infect. 2011 Nov;41(11):594-601
references.pmid: 22036519
references.citation: Appl Environ Microbiol. 2011 Dec;77(23):8325-35
references.pmid: 21984240
references.citation: Arch Intern Med. 1997 Feb 24;157(4):425-30
references.pmid: 9046894
references.citation: J Infect Dis. 1959 Mar-Apr;104(2):164-73
references.pmid: 13654805
references.citation: Medicine (Baltimore). 1998 Sep;77(5):313-36
references.pmid: 9772921
references.citation: Medicine (Baltimore). 2000 Nov;79(6):360-8
references.pmid: 11144034
references.citation: Nat Rev Microbiol. 2010 Sep;8(9):645-55
references.pmid: 20706281
references.citation: Trends Microbiol. 2012 Aug;20(8):360-8
references.pmid: 22652164
references.citation: J Infect Dis. 1953 Nov-Dec;93(3):247-56
references.pmid: 13109239
references.citation: Vet Microbiol. 2008 Aug 25;130(3-4):320-9
references.pmid: 18355992
references.citation: Eur J Clin Microbiol. 1986 Apr;5(2):169-71
references.pmid: 3087749
references.citation: Neuropathol Appl Neurobiol. 2011 Dec;37(7):753-67
references.pmid: 21486315
references.citation: Cell Biol Int. 2009 Feb;33(2):187-91
references.pmid: 19032985
references.citation: FEMS Immunol Med Microbiol. 2008 Jul;53(2):151-65
references.pmid: 18462388
references.citation: Vet Q. 2000 Oct;22(4):212-6
references.pmid: 11087133
references.citation: Appl Environ Microbiol. 2004 Nov;70(11):6887-91
references.pmid: 15528558
references.citation: Semin Neurol. 2000;20(3):361-73
references.pmid: 11051300
references.citation: J Virol. 1998 Nov;72(11):8463-71
references.pmid: 9765382
references.citation: J Cell Biol. 1990 Dec;111(6 Pt 2):2979-88
references.pmid: 2125302
references.citation: Comp Immunol Microbiol Infect Dis. 2012 Sep;35(5):429-41
references.pmid: 22537479
references.citation: Clin Infect Dis. 1993 May;16(5):689-702
references.pmid: 8507761
references.citation: Microbes Infect. 2007 Aug;9(10):1176-87
references.pmid: 17720603
references.citation: Neurochem Int. 2010 May-Jun;56(6-7):727-35
references.pmid: 20206655
references.citation: Microbes Infect. 2013 Dec;15(14-15):971-80
references.pmid: 24144539
references.citation: Infect Immun. 1994 Feb;62(2):543-53
references.pmid: 8300212
references.citation: Sci Rep. 2012;2:786
references.pmid: 23139859
references.citation: Schweiz Arch Tierheilkd. 1997;139(8):354-62
references.pmid: 9297232
references.citation: Vet Pathol. 1977 Jul;14(4):297-313
references.pmid: 560741
references.citation: Nat Rev Microbiol. 2006 Jun;4(6):423-34
references.pmid: 16710323
references.citation: Vet J. 1997 Jan;153(1):9-29
references.pmid: 9125353
references.citation: Acta Neuropathol. 2010 May;119(5):617-30
references.pmid: 20119836
references.citation: Emerg Infect Dis. 2002 Mar;8(3):305-10
references.pmid: 11927029
references.citation: Clin Infect Dis. 1995 Jan;20(1):66-72
references.pmid: 7727673
references.citation: Virulence. 2012 Mar-Apr;3(2):213-21
references.pmid: 22460636
references.citation: Brain Pathol. 2005 Jul;15(3):187-91
references.pmid: 16196384
references.citation: Eur J Immunol. 2005 Aug;35(8):2486-95
references.pmid: 16025565
references.citation: mBio. 2014 Apr 15;5(2):e00025
references.pmid: 24736221
references.citation: Curr Top Microbiol Immunol. 2009;330:3-30
references.pmid: 19203102
references.citation: EFSA J. 2018 Dec 12;16(12):e05500
references.pmid: 32625785
references.citation: Acta Microbiol Hung. 1989;36(2-3):125-31
references.pmid: 2517159
references.citation: MMWR Morb Mortal Wkly Rep. 2013 Jun 7;62(22):448-52
references.pmid: 23739339
references.citation: Appl Environ Microbiol. 2010 Jun;76(11):3625-36
references.pmid: 20363781
references.citation: Schweiz Arch Tierheilkd. 1969 Nov;111(11):622-41
references.pmid: 4983825
references.citation: Nat Methods. 2008 Jul;5(7):605-7
references.pmid: 18536722
references.citation: Adv Virus Res. 2011;79:33-53
references.pmid: 21601041
references.citation: Interdiscip Perspect Infect Dis. 2010;2010:632513
references.pmid: 20204066
references.citation: Int J Food Microbiol. 2007 Jan 1;113(1):1-15
references.pmid: 17010463
references.citation: J Neurosci Res. 2007 Sep;85(12):2529-37
references.pmid: 17387705
references.citation: J Virol. 1996 Apr;70(4):2191-200
references.pmid: 8642642
references.citation: Trends Microbiol. 2015 May;23(5):283-8
references.pmid: 25639651