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 Streptococcus (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.
- Wayne CR, Bremner L, Faust TE, Duran-Laforet V, Ampatey N, Ho SJ, Feinberg PA, Arvanitis P, Ciric B, Ruan C, Elyaman W, Delaney SL, Vargas WS, Swedo S, Menon V, Schafer DP, Cutforth T, Agalliu D. Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis. bioRxiv 2023 Mar 10;532135. doi: https://doi.org/10.1101/2023.03.10.532135
- 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 USA 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.
Human genetic studies aimed at understanding and treating pediatric autoimmune disease.
Using 21st century breakthroughs in human gene sequencing technology and statistical approaches, we are investigating whether discrete genetic loci predispose a small subset of children to develop PANS/PANDAS or Sydenham’s chorea, collectively known as basal ganglia encephalitis (BGE). In collaboration with Hakon Hakonarson’s group at the Center for Applied Genomics, Children’s Hospital of Philadelphia, we are in the midst of a large-scale recruitment and sequencing effort, employing both GWAS and whole-exome methods. Our initial candidates arising from the first 60 cases reveal several genes that appear to regulate immune function, and we are using our mouse model for post-Streptococcal BGE to validate these candidate genes and determine their mechanistic roles during the course of disease.
In a second project, we have identified a robust serum profile of 19 signature cytokines and growth factors that are associated with PANS/PANDAS, representing the first biomarker for this enigmatic disease and promising to revolutionize its diagnosis, treatment monitoring and ultimately novel therapeutic targets.
Mechanisms of CNS infiltration by immune cells following S. pyogenes infection.
Autoimmune encephalitides (AE) are complex disorders of the central nervous system (CNS) caused by autoantibodies that recognize neuronal proteins as foreign antigens, resulting in motor disturbances, seizures and psychiatric disorders. The targets of a number of pathologic autoantibodies have been identified for AE, but little is known about how these antibodies bypass the blood-brain barrier (BBB) to cause disease. Infiltrating T cells have been identified in the brains of AE patients, but their role in disease pathogenesis is poorly understood. Group A Streptococcus (GAS) infections are known to cause autoimmune sequelae in the CNS in the form of Sydenham’s chorea (SC), which may be caused by anti-dopamine receptor autoantibodies, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). In the Agalliu lab, Charlotte uses an animal model of SC/PANDAS to study the effects of immune cell infiltration of the CNS following multiple intranasal infections, with a specific focus on the contribution of Th17 cytokines to neuropathology and BBB dysruption.
Research from Dr. Agalliu’s laboratory in the Department of Neurology at Columbia University Irving Medical Center has recently shown that the olfactory route can be used as gateway to the CNS by immune cells in an animal model. (PANDAS Network)
Pat Cleary and Dritan Agalliu discuss their collaboration to investigate the link between the generation of GAS-specific Th17 cells and CNS autoimmunity. (Journal of Clinical Investigation)
Our research on PANDAS is made possible by donations to the lab’s PANDAS Research Fund.