Bacterial and Toxin Engineering to Treat Motor Neuron Degeneration

Mammalian hosts are constantly exposed to gut-resident bacteria and to bacterial pathogens in the environment. It is increasingly clear that bacteria can signal to the nervous system to regulate neurophysiology, CNS inflammation, and neurodegeneration. Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron degenerative disease with few effective treatments. In this project, we investigate the role that bacteria play in regulating neurodegeneration in ALS. Our major goals in this project are to: a) Determine whether the gut microbiome alters inflammation, neuronal loss, and disease progression in ALS mice; b) Determine whether bacterial infections trigger neurodegeneration; and c) Engineer a specific bacterial toxin to deliver pro-survival factors into motor neurons to treat ALS. Utilizing bacterial manipulation or engineering their toxins to modulate neurotoxicity could be transformative approaches to treat devastating motor neuron diseases.

The team made exciting progress to develop engineered bacterial toxins to target molecular cargoes into the nervous system. They found that the anthrax toxin system, which consists of protective antigen (PA), lethal factor (LF) and edema factor (EF) can deliver molecular cargoes into peripheral sensory neurons to block pain signaling (Yang et al, Nature Neuroscience 2021). They are engineering this system to deliver cargoes into other neuronal subsets with an aim to target neurodegeneration.