Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells
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
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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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 4

T cell infiltration into the brain is associated with BBB leakage.

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T cell infiltration into the brain is associated with BBB leakage. (A an...
(A and F) Heatmaps of biocytin-TMR leakage in the OB (A) and posterior brain (F) in SJL/J mice after multiple GAS inoculations at 6 and 48 hours after the last inoculation, respectively. Red hues represent the percentage of animals showing brain leakage, not the intensity of biocytin-TMR leakage (see legend in A). Glom, glomerular; Gran, granular; Amyg, amygdala. Yellow boxes in A and F outline the regions shown in the micrographs in B–E and G–J. Representative images of biocytin-TMR leakage from blood vessels into granular and glomerular layers of the OB (B–E), LH (G and I), and amygdala (H and J) in GAS-inoculated and naive mice. Arrowheads depict neuronal uptake of the tracer. Anti–caveolin 1 (green) labels blood vessels in all sections. (K–M) Bar graphs compare the fold change in biocytin-TMR average intensity between multiply GAS-inoculated and naive mice (dashed black line) in the OB, LH, and amygdala (H) or in other CNS regions (AON, OT, PC, and DG) (I) 6 hours (black bars) and 48 hours (gray bars) after the last inoculation. Baseline fluorescence intensity in naive animals is represented with a dashed black line. Data were collected from 3 independent experiments for 3 to 8 animals and are presented as the mean ± SEM. *P < 0.05 and **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test comparison between GAS-inoculated and naive animals. Scale bars: 50 μm (B–E and G–J).