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 3

Streptococcus-specific brain-derived T cells express cytokines similar to those derived from NALT.

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Streptococcus-specific brain-derived T cells express cytokines similar t...
(A) Representative FACS plots and (B) bar graphs showing cytokine profiles and the distribution of 2W:I-Ab+ CD4+ T cells isolated from brain, NALT, or CLNs from GAS-2W i.n. inoculated C57BL/6 mice. Data were collected from 3 independent experiments for 4 animals and represent the mean ± SEM. (C) Bar graphs showing the the total number (CD4+; black) and bacterium-specific (2W:I-Ab+ CD4+; gray) T cells in brains from mice inoculated either i.n. (n = 5) or i.v. (n = 3) with HK-GAS or from naive controls (n = 1). Data represent the mean ± SEM. (D) FACS plots of CD44hiCD4+ T cells isolated from brains of either naive or HK-GAS-inoculated mice that were activated for 3 hours ex vivo with PMA+I prior to IL-17A and IFN-γ analysis. Gray arrow shows the percentage of bacterium-specific (2W:I-Ab+) T cells that expressed either IL-17A or IFN-γ.