Virus-Induced Changes in Non-Immune Signaling by MHCI: Effects on Viruses as Tools and in Cancer Risks

Abstract

Proteins of the major histocompatibility complex class I (MHCI) are known for their central role in the immune response. However, studies over the last twenty years have revealed that MHCI proteins also have unexpected, non-immune functions in the nervous system. While MHCI’s non-immune functions are increasingly clear, almost nothing is known about the potential for neuro-immune crosstalk given MHCI’s distinct roles in the two systems. Because of MHCI’s important role in the immune system, viruses are known to interfere with its expression, which in turn may affect its non-immune functions. In this thesis, I focus on adeno-associated viruses (AAVs), a virus widely used in neuroscientific studies and gene therapy vectors. First, we show that AAV reduces dendritic length and complexity in somatosensory cortex. We also show that MHCI immune protein levels are upregulated in AAV-injected brain regions. In order to determine whether complement 3, another immune protein is implicated in the dendritic simplification, we analyze activated microglia which is used in complement pruning. Finally, I expand this thesis into a literature review of common viruses and their effects on MHCI, focusing specifically on oncogenic viruses. A better understanding of how viruses and cancers affect MHCI’s newly-discovered, non-immune functions is critical to optimizing viruses as research and clinical tools, and may shed an unexpected light on the mechanisms by which viral infections increase cancer risk.