Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

Dileepan, Thamotharampillai; Smith, Erica D.; Knowland, Daniel; Hsu, Martin; Platt, Maryann; Bittner-Eddy, Peter; Cohen, Brenda; Southern, Peter; Latimer, Elizabeth; Harley, Earl; Agalliu, Dritan; Cleary, P. Patrick

doi:10.1172/jci80792

Cited by 128Streptococcal Infections and TreatmentsT-cell and B-cell ImmunologyBacterial Infections and Vaccines

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

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Dileepan, Thamotharampillai, Smith, Erica D., Knowland, Daniel, Hsu, Martin, Platt, Maryann, Bittner-Eddy, Peter, Cohen, Brenda, Southern, Peter +4 more·2015·Journal of Clinical Investigation

DOI 10.1172/jci80792PMC PMC4701547

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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.

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The pathophysiology of IAE is believed to involve an autoimmune process that targets brain structures including the basal ganglia, leading to neuroinflammation and subsequent neuropsychiatric symptoms.
“The pathophysiology of IAE is believed to involve an autoimmune process that targets brain structures including the basal ganglia, leading to neuroinflammation and subsequent neuropsychiatric symptoms.”
From An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know (2023) · cites this paper as [15]
The section “Why do T cells home to and persist in the brain?” proposes that repeated streptococcal infections may allow autoreactive antibodies into the brain and contribute to neuropsychiatric symptoms. But this is a proposed model for SC and PANDAS, not an account of IAE; the authors also report no extensive blood–brain barrier damage or IgG deposition in the basal ganglia of their mice. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Streptococcus-specific T H 17 cells in the CNS that remain after repeated intranasal infections increase permeability of capillaries in proximity to the olfactory bulb, amygdala, and hypothalamus.
“Streptococcus-specific T H 17 cells in the CNS that remain after repeated intranasal infections increase permeability of capillaries in proximity to the olfactory bulb, amygdala, and hypothalamus.”
From An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know (2023) · cites this paper as [15]
Figure 4 and the Discussion report increased blood–brain barrier leakage near the olfactory bulb, amygdala, and lateral hypothalamus after repeated intranasal GAS inoculations. The Discussion argues that infiltrating GAS-specific Th17 cells are the primary cause, but presents that mechanism as an inference; the paper also says it could not distinguish T cells retained from earlier infections from newly arriving cells. (LLM, conf=0.85)
Experimental — accuracy not yet measured
This causes disruption of tight junctions that are essential to maintaining the integrity of the BBB, allowing infiltration with immunoglobulin (Ig) G and anti-CNS autoantibodies.
“This causes disruption of tight junctions that are essential to maintaining the integrity of the BBB, allowing infiltration with immunoglobulin (Ig) G and anti-CNS autoantibodies.15”
From An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know (2023) · cites this paper as [15]
The paper reports that repeated GAS inoculation in mice was associated with disrupted endothelial tight junctions, BBB leakage, and increased brain IgG (Results, “GAS-specific Th17 cells in the brain likely originate from NALT”; Discussion). It proposes that this could give autoantibodies access to CNS targets, but does not establish that anti-CNS autoantibodies infiltrated the brain; the claim states that proposed consequence as fact. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Mouse models currently indicate how intranasal infections with bacteria can polarize T cells toward a T H 17 phenotype owing to production of 2 proinflammatory cytokines, interleukin (IL)-6, and transforming growth factor-b1.
“Mouse models currently indicate how intranasal infections with bacteria can polarize T cells toward a T H 17 phenotype owing to production of 2 proinflammatory cytokines, interleukin (IL)-6, and transforming growth factor-b1.15”
From An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know (2023) · cites this paper as [15]

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Authors: Dileepan, T., Smith, E. D., Knowland, D., Hsu, M., Platt, M., Bittner-Eddy, P., Cohen, B., Southern, P., Latimer, E., Harley, E., Agalliu, D., & Cleary, P. P.
Affiliations: University of Minnesota (US)
University of California, Irvine (US)
Columbia University Irving Medical Center (US)
Georgetown University (US)
Corresponding author: Agalliu, Dritan
Cleary, P. Patrick
ORCID: Dileepan, Thamotharampillai
Smith, Erica D.
Knowland, Daniel
Hsu, Martin
Platt, Maryann
Southern, Peter
Harley, Earl
Agalliu, Dritan
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2015-12-14
Volume: 126
Issue: 1
Pages: 303-317
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci80792
PMC: PMC4701547
OpenAlex: W2208060404
Cited by: 128
References: 64
Citations by year: 2026: 12 · 2025: 12 · 2024: 9 · 2023: 18 · 2022: 12 · 2021: 9 · 2020: 13 · 2019: 9 · 2018: 6 · 2017: 18 · 2016: 10
FWCI: 12.15
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Multiple Sclerosis Society (RG4673A1/1)
University of Minnesota
Multiple Sclerosis Society
National Institutes of Health (CA-62203)
University of California, Irvine (CA-62203)
National Heart, Lung, and Blood Institute (R01HL116995, HL116995-01)
National Cancer Institute (CA 62203, P30CA062203)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Streptococcal Infections and Treatments
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords: Streptococcus pyogenes, streptococcal infection, Th17 cells, intranasal infection, blood-brain barrier disruption, central nervous system autoimmunity, autoantibody cross-reactivity, nasal-associated lymphoid tissue, tonsil, CD4+ T cell migration, microglial activation, olfactory bulb, neuropsychiatric complications
MeSH terms: Animals, Blood-Brain Barrier, Brain, Cell Movement, Female, Immunoglobulin G, Interferon-gamma, Mice, Inbred C57BL, Streptococcus pyogenes, Palatine Tonsil, CD4-Positive T-Lymphocytes, Tight Junctions, Interleukin-17, Mice, Th17 Cells

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Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

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