Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells
Thamotharampillai Dileepan, … , Dritan Agalliu, P. Patrick Cleary
Thamotharampillai Dileepan, … , Dritan Agalliu, P. Patrick Cleary
Published December 14, 2015
Citation Information: J Clin Invest. 2016;126(1):303-317. https://doi.org/10.1172/JCI80792.
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Research Article Immunology

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

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

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Figure 6

T cell accumulation in the OB is accompanied by loss of vesicular excitatory synaptic proteins.

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T cell accumulation in the OB is accompanied by loss of vesicular excita...
(A–H) Immunofluorescence images of olfactory glomeruli stained for the vesicular marker vGluT2 (red) and GAD67 (green, A–D) or PSD95 (green, E–H). Scale bars: 15 μm (A, C, E, and G) and 5 μm (B, D, F, and H). (I) Bar graphs of fluorescence intensity for vGluT2, GAD67, and PSD95 within glomeruli. Data were collected from 3 to 5 mice in 2 independent experiments and represent the mean ± SEM. ***P ≤ 0.001, by 1-way ANOVA with Tukey’s post-hoc multiple comparisons test. (J) Simplified diagram of the synaptic circuitry within olfactory glomeruli, which receive excitatory input from the nose via vGluT2-expressing olfactory sensory neurons (ON). Olfactory information is modulated by inhibitory interneurons (IN) that express GAD67 before it is relayed to posterior parts of the brain, including limbic regions. PSD95 (blue) is expressed in the postsynaptic component of mitral or tufted cell dendrites within the olfactory glomeruli that make connections with olfactory sensory axons. The number of vGluT2 vesicles in the presynaptic component (olfactory sensory axons) is reduced after repeated i.n. GAS infections.