Academic Commons

Theses Doctoral

Cellular Mechanisms of Neurovascular Breakdown and Neuronal Dysfunction Following Recurrent Group A Streptococcus Infections in Mice

Platt, Maryann P.

Autoimmune encephalitic (AE) syndromes represent a unique manifestation of autoimmunity: the immune system recognizes the brain as foreign, and interferes with neuronal function. AE syndromes are characterized by hallucinations, paranoia, anxiety, seizures, and autonomic dysregulation, and progress over a matter of weeks as autoantibodies targeting the brain bind more densely to their CNS targets. Development of AE has been linked to peripheral tumors and infection, both of which provide structural mimetics to CNS antigens to incite an immune response in the periphery. How these brain-specific antibodies reach the CNS remains unclear.

In rare cases, Group A Streptococcus (GAS, S. pyogenes) infections can cause CNS autoimmunity targeting the basal ganglia, termed post-infectious basal ganglia encephalitis (BGE), manifesting as motor (Sydenham’s chorea) and psychiatric (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus, PANDAS) abnormalities. In a mouse model of post-infectious BGE, we have shown that repeated intranasal GAS infections generate robust T cell infiltration into the CNS, concomitant with blood-brain barrier breakdown, microglial activation, and olfactory synapse degradation. However, the different T cell subtypes that enter the brain, how they enter the CNS, and their relative contributions to neural dysfunction and neuroinflammation remain unclear.

Th17 lymphocytes are heavily implicated in many autoimmune diseases, but whether the inflammatory post-infectious BGE reaction induces functional deficits in odor processing and requires Th17 lymphocytes was unknown. Here we demonstrate that mice lacking Th17 lymphocytes display both reduced BBB impairment and antibody infiltration. Furthermore, multiple GAS infections induce deficits in odor processing, which are partially ameliorated in Th17 cell-deficient mice. Notably, neuroinflammation and some excitatory synaptic loss persist, due to the presence of Th1 lymphocytes. Th17 lymphocytes are therefore critical for both selective CNS entry of autoantibodies and neural circuit impairment during post-infectious BGE. By examining the regulation of chemokine ligand expression in GAS-inoculated mice, we determined that CCL20/CCR6 and CCL2/CCR2 chemokine axes are implicated in T cell homing to the brain. In chemokine receptor mutant CCR6+/- CCR2-/- mice, T cell infiltration is reduced by 86.2%, and microglial activation is blunted. These findings suggest that CCL2/CCR2 and CCL20/CCR6 signaling may play a role in T cell homing to the brain and neuroinflammation. Finally, we first assessed behavioral and immune responses in two different GAS exposure models. It was clear that while behavioral abnormalities can be recapitulated in mice given subcutaneous GAS immunizations, this elicited relatively weak cellular and humoral immune responses. By contrast, mice given intranasal GAS inoculations showed minimal behavioral abnormalities, but elicited robust humoral and cellular immune responses.

Taken together, these data demonstrate the pivotal role of Th17 lymphocytes in brain pathology and olfactory processing deficits after recurrent GAS infections in our mouse model. Our intranasal inoculation model supports the conclusion that post-infectious BGE is autoimmune in nature, despite the absence of behavioral symptoms in this model. Using multiple mouse models of post-infectious BGE may allow us to study distinct facets of disease pathogenesis. Finally, this work underscores the ability of T cells to incite neuroinflammation, provides a useful clinical diagnostic test in olfactory functional assessments, and lends support to T cell immunotherapy strategies in patients with post-infectious BGEs.

Files

This item is currently under embargo. It will be available starting 2021-05-29.

More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Agalliu, Dritan
Degree
Ph.D., Columbia University
Published Here
July 31, 2019
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.