Past Research

Recombinant adeno-associated viruses (AAVs) have revolutionized neuroscience research and are used to deliver human gene therapies to the nervous system. While antiviral immunity can cause viral clearance and tissue damage in the periphery, AAV isn’t associated with significant inflammation in the immune privileged context of the central nervous system (CNS). However, the possibility that AAV has sub-toxic effects on circuit structure or function had not been explored. In my postdoctoral research, I found that AAV simplifies dendritic arbors of cortical pyramidal cells in a TLR9-dependent manner. Because there are currently two FDA-approved AAV therapeutics being administered to patients, it is critical to understand the role of the antiviral immune response in disrupted neuronal homeostasis and its effects on circuit function.

Future Research

My lab is interested in studying how host immune responses to neurotropic viruses can disrupt circuit structure, function and development. 

Goal - understanding the role of pleiotropic immune molecules in brain development and function during normal and pathological conditions
Critical periods during brain development are regulated, in part, by certain immune molecules. How can viral infections, which may disrupt these immune molecule levels, affect brain development? Also, how does neuro-immune crosstalk regulate normal brain function and development in the absence of infection?

Previous research identifying the role of immune molecules in the nervous system has relied on transgenic knockout mice. Zebrafish offer several practical advantages to mouse models, including higher fecundity, clear tissue for microscopy, quick development and smaller size. We plan to use zebrafish to study how immune proteins contribute to neural development and how immune challenges during brain development can impact neural circuits.

Goal - improving the safety and efficacy of viral vectors for neuroscience research and human gene therapy

Recombinant adeno-associated viruses (rAAV) are used in human gene therapy to treat monogenic disorders and in neuroscience research to study a broad range of neurological disorders. How can we make viral vector use in the central nervous system safer and more effective?
  • The role of microglia and T cells in virally-induced dendritic loss
In the developing visual system, microglia phagocytose synapses that have been marked by members of the complement cascade.  We observe upregulation of the complement cascade and microglial activation four days after AAV injection in vivo. Although neurons can express TLR9 and therefore could potentially detect AAV, our preliminary in vivo and in vitro data suggest that dendritic loss in cortical neurons is not cell autonomous. The most likely candidate drivers of dendritic loss in pyramidal cells after AAV injection are microglia.
Candidate cell types driving dendritic loss also include peripheral immune cells. In the periphery, activation of the adaptive immune response limits AAV efficacy and transgene expression as MHCI proteins present antigens to surveilling cytotoxic CD8+ T cells and B cells produce anti-AAV neutralizing antibodies. We observe persistent MHCI upregulation after injection of AAV. However, in the CNS, it is unknown if MHCI and T cell interactions could be responsible for AAV-induced dendritic loss. 
  • How do DNA and RNA viruses differentially affect nervous system function?
In addition to DNA-based AAVs, RNA viruses, such as recombinant lentivirus, are widely used in neuroscience research and are candidate vectors for human gene therapy. One advantage of lentivirus-mediated gene delivery over AAV-mediated gene delivery is the increased cargo size, which allows for the delivery of larger/more transgenes and regulatory sequences to neurons. However, lentiviruses are more immunogenic than AAV and integrate into the host genome, raising the possibility of insertional mutagenesis. RNA viruses are detected by TLR7, whose signaling cascades quickly converge with those of TLR9, thus there may be common disruptions to neuronal homeostasis between RNA and DNA-based viruses. 

The role of Toll-like receptors in neuronal function and behavior
  • We are also currently studying the role of Tol-1, a homolog of Toll-like receptors in C. elegans, in neuronal function and behavior. 


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