How does repeated Streptococcus pyogenes infection induce rapid onset of neuropsychiatric symptoms in children?
Despite emerging evidence that inflammatory molecules (e.g. cytokines and complement) alter synapse formation, neuronal connectivity and behavior, the molecular mechanisms underlying impairment of brain development and function by infections that induce an aberrant immune response remain poorly understood.
Group A Streptococci (S. pyogenes; GAS), the primary agent for acute pharyngitis in children, is associated with several autoimmune diseases, including the central nervous system (CNS) autoimmune motor and behavioral disorders Sydenham’s chorea and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). Recurrent GAS mucosal infections induce a strong antigen-specific Th17 cellular response in mice and humans. Th17 cells have been implicated in many autoimmune diseases including multiple sclerosis, where they trigger inflammation and destruction of the blood-brain barrier (BBB).
Our preliminary experiments show that these T cells specifically home to the brain, localizing primarily in the olfactory bulb (OB) and along the olfactory nerve as well as some other brain regions where OB neurons send projections and eventually make synaptic connections. We are investigating the mechanisms of how these T cells induce neuronal damage and BBB breakdown and the consequences for behavioral outcomes.
- Platt MP, Bolding KA, Wayne CR, Chaudhry S, Cutforth T, Franks KM, Agalliu D. (2020) Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis. Proc Natl Acad Sci U S A Mar 24;117(12):6708-6716.
- Platt MP, Agalliu D, Cutforth T. (2017) Hello from the Other Side: How Autoantibodies Circumvent the Blood-Brain Barrier in Autoimmune Encephalitis. Front Immunol 8:442
- Cutforth T, DeMille MM, Agalliu I, Agalliu D. (2016) CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors. Future Neurol 11(1):63-76
- Dileepan T, Smith ED, Knowland D, Hsu M, Platt M, Bittner-Eddy P, Cohen B, Southern P, Latimer E, Harley E, Agalliu D, Cleary PP. (2016) Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells. J Clin Invest 126(1):303-17
Our research on PANDAS is made possible by donations to the lab’s PANDAS Research Fund.