title: Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells.
abstract: Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.
authors.forename: Thamotharampillai
authors.initials: T
authors.lastname: Dileepan
authors.forename: Erica D
authors.initials: ED
authors.lastname: Smith
authors.forename: Daniel
authors.initials: D
authors.lastname: Knowland
authors.forename: Martin
authors.initials: M
authors.lastname: Hsu
authors.forename: Maryann
authors.initials: M
authors.lastname: Platt
authors.forename: Peter
authors.initials: P
authors.lastname: Bittner-Eddy
authors.forename: Brenda
authors.initials: B
authors.lastname: Cohen
authors.forename: Peter
authors.initials: P
authors.lastname: Southern
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Latimer
authors.forename: Earl
authors.initials: E
authors.lastname: Harley
authors.forename: Dritan
authors.initials: D
authors.lastname: Agalliu
authors.forename: P Patrick
authors.initials: PP
authors.lastname: Cleary
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D014066:Palatine Tonsil / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D058504:Th17 Cells / Q000502:physiology*; D019108:Tight Junctions / Q000502:physiology
chemical_list: D007074:Immunoglobulin G; D020381:Interleukin-17; D007371:Interferon-gamma