Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.

Adviser: Akiko Iwasaki.

Herpes simplex virus (HSV) is a major human pathogen that persistently infects over 3 billion humans worldwide and costs $2 billion in annual healthcare expenditures in the United States alone. In my thesis, I utilized a physiologically relevant mouse HSV infection model in order to explore the complex relationships between HSV infection, the host innate immune response, and the development of HSV-dependent disease states. Here, I present and discuss the major findings of my thesis work.

Type I interferons (IFNs) are considered to be the universal mechanism by which viral infections are controlled. However, many IFN-stimulated genes (ISGs) rely on antiviral pathways that are for the most part toxic to host cells, which may be detrimental in nonrenewable cell types, such as neurons. I show that dorsal root ganglionic (DRG) neurons produced and respond little to type I IFNs to control infection with herpes simplex type 1 (HSV-1). I found that DRG neurons required autophagy to limit HSV-1 replication both in vivo and in vitro. In contrast, mucosal epithelial cells and other mitotic cells responded robustly to type I IFNs and did not require autophagy to control viral replication. These findings imply a fundamental difference in the innate antiviral strategies employed by neurons and mitotic cells to control HSV-1 infection.

I also find that introduction of HSV-1 into the mouse genital tract results in neuron-dependent entry of HSV-1 to the transverse and descending colon. This results in a binary, HSV-dependent effect on the inflammatory environment of the host colon. Our findings demonstrate that chronic, persistent viral infections such as HSV-1 that are not typically associated with the intestinal tissues can influence the inflammatory environment of the colon and may play a role in the development, severity, or progression of human disease states with an inflammatory driver such as inflammatory bowel disease (IBD).

Finally, I investigated the consequences of HSV acute replication within the host peripheral nervous system and present evidence that HSV replication within the peripheral nervous system (PNS) can antagonize autonomic function. I observed that HSV infection induces time-dependent, pathological enlargement of the colon due to a failure to transmit proper autonomic nervous system signals that mediate gut peristalsis and defecation. Thus, deregulation of the autonomic nervous system can occur during HSV infection and may have underappreciated pathophysiological consequences.