Herpes Simplex Virus 1 (HSV-1) is best known as the virus that causes cold sores, but it is also the leading infectious cause of blindness in the United States.
In the eye, HSV-1 can produce recurrent corneal infections that culminate in neurotrophic keratitis—a devastating disease in which the cornea progressively loses its sensory nerves. Without these nerves, even minor injuries fail to heal, leaving patients vulnerable to chronic ulcers, scarring, and permanent vision loss.
Despite decades of research, one fundamental question remains unanswered: What causes these nerves to die following infection with HSV-1? To date, work has largely focused on the immune responses that develop days after infection and fail to examine early events following HSV-1 infection that could initiate the process of nerve loss in the eye.
The novel work being done in the Brandt Lab at the University of Wisconsin (UW)—Madison offers a novel and paradigm-shifting hypothesis, that Wallerian Degeneration (WD) is responsible for this nerve loss following HSV-1 infection in the eye. Wallerian Degeneration is a highly conserved mechanism that involves neuronal pruning following damage or trauma, such as what happens in an ocular HSV-1 infection.
The Brandt Lab had proposed the novel hypothesis that that WD is responsible for corneal sensory nerve loss and that it is initiated very early after HSV-1 infection. To explore this further, the lab has, together with the Neumann Lab, also at UW—Madison, developed an innovative cell culture model system of WD that, combines a novel collection of recombinant viruses with different degrees of virulence with this new model to map viral genes involved in driving WD and identify the mechanisms involved in nerve loss.
Excitingly, the Brandt and Neumann labs have just received a 4-year R01 from the National Eye Institute to explore these novel and paradigm shifting hypotheses. They will use a novel set of recombinant HSV-1 from the Brandt laboratory and an innovative neuronal cell culture system from the Neumann laboratory to identify viral genes that drive the axon loss.
They will also use mice lacking two critical genes to confirm WD is the process for axon loss and investigate the possible role of innate immune system in the loss of sensory nerve axons in the cornea. This work will provide important information for developing a combination therapy to block the virus and prevent WD.