Immune-mediated Neurological Injury: Insights from a Zebrafish Model of Leprosy
How do microbes interact with the nervous system? A surprising number of microbial infections can change functions of the nervous system. For example, the bacteria that cause leprosy prevent pain sensation in the skin, bacterial meningitis causes neuronal injury, and congenital infections can slow neurodevelopment. How do pathogens cause these neurological responses? That’s often challenging to determine, because interactions between microbes and neurological tissue can occur deep within organs – like the brain – that are difficult to directly observe in a living animal.
Our lab uses zebrafish larvae, which are optically transparent, to directly observe microbes as they infect the neurons, glia, blood vessels, and phagocytes of neurological tissue. The overarching goals of our research are to: (1) define the mechanisms by which infecting microbes change nervous system functions, (2) determine the roles of inflammation in microbe-nervous system interactions, and (3) explore how the nervous system can change the course of infection.
One focus of our lab is using leprosy to understand how inflammation damages nerves. The stigmatizing deformities of leprosy, such as loss of fingers and blindness, are a direct consequence of widespread nerve damage that is unique to this ancient disease. Today, Mycobacterium leprae, the bacteria that cause leprosy, infect almost a million people. Despite this, how M. leprae damages nerves remains incompletely understood. This is largely due to the paucity of animal models for infection by M. leprae, which are notoriously fastidious bacteria that cannot be grown outside of a live animal.
Our lab models M. leprae infection in zebrafish, which are housed at the same cool temperatures required for M. leprae to grow. Zebrafish larvae are small (about 1 millimeter) and optically transparent. This allows for real-time observation of microbes, cells, or genetically altered molecules in an intact animal. The zebrafish leprosy model enabled the surprising discovery that an unusual M. leprae lipid activates cells of the immune system to damage nerves. In particular, the cellular “batteries” of nerve axons, called mitochondria, were damaged by M. leprae infection. These studies established the importance of inflammation in early leprosy nerve damage. Further, they suggest that mitochondrial dysfunction, a recurrent theme in neurodegenerative conditions, may also contribute to nerve damage in leprosy.
To more precisely understand the connection between inflammation and mitochondrial injury, we are investigating the mechanisms by which M. leprae damages mitochondria. In cultured cells, M. leprae activates STING, a protein activated by the DNA that leaks from damaged mitochondria. Activation of STING by M. leprae may explain why mutations in the PARK2 and LRRK2 genes, which are required for disposing of damaged mitochondria, are associated with increased susceptibility to leprosy. Intriguingly, mutations in PARK2 and LRRK2 cause another disease that features STING activation, neuronal injury, mitochondrial damage and inflammation: Parkinson’s disease. The goal of these studies is to clarify this surprising genetic association between leprosy and Parkinson’s disease, and provide a more comprehensive understanding of the sources of damaging inflammation in leprosy, which may provide new targets for the development of therapies to control neuroinflammation.