Charles L. Howe, Ph.D.

Overview
My research is focused on the role of the immune system in the injury of axons and neurons within the central nervous system (CNS). My lab studies the effects of acute CNS infection with the Theiler's picornavirus in an effort to understand the interaction of both innate (neutrophils and natural killer cells) and adaptive (CD8+ and CD4+ T cells) immune effectors with infected or stressed neurons. We also use the Theiler's virus as a model for chronic demyelination of the spinal cord and as a tool for studying the role of innate and adaptive immune effectors in the axon injury that occurs consequent to demyelination. Our work has relevance to the prevention and control of CNS viral infections and to the prevention or alleviation of functional disability associated with demyelinating diseases such as multiple sclerosis (MS). As a basic scientist, I am primarily interested in understanding how the immune system invades, attacks, and injures neurons and axons. As a translational scientist, I am primarily interested in the design and discovery of novel mechanisms for preventing or ameliorating the loss of neurological function that is currently an inevitable and irreversible consequence of demyelination.

Specific Research Topics Identification of the immune effector(s) responsible for axonal injury during chronic demyelination of spinal axons. We are currently using genetic mouse models to dissect the effector molecules and cells responsible for axon injury during demyelination. Our most recent findings indicate that perforin is an effector molecule that is critical for the loss of axons and neurologic function that occurs in chronically demyelinated mice. Ongoing experiments seek to identify the immune cell responsible for the release of perforin, with a specific focus on CD8+ cytotoxic T cells and natural killer cells.

Identification of the mechanisms of neuronal injury and death during acute CNS viral infection. The hippocampus undergoes a severe and stereotypical injury response to acute infection with Theiler's virus. We are using several approaches, including genetic mouse models, bone marrow chimeric mice, and primary neuronal culture models to determine when, how, and why neurons die during acute picornavirus infection. Our most recent findings indicate that neurons experience oxidative stress that induces apoptosis independent of direct virus infection, and that this injury is not dependent upon an adaptive immune response but may require innate immune effectors.

Identification of age-related changes in the immune effectors that respond to acute CNS viral infection. We have recently discovered very exciting age-related changes in the immune response to acute viral infection that have significant repercussions for neuronal injury and viral clearance.

Identification of novel stress-related immune-recruitment cues expressed by infected or demyelinated neurons. An important component of the research in my lab is directed at the discovery of signals or cues that are expressed by stressed neurons and axons and that initiate or potentiate immune-mediated attack and injury. Our recent experiments have identified several MHC class I-related molecules that may serve as ligands for the NKG2D immune receptor found on natural killer cells and cytotoxic T cells.

Characterization of the mechanisms involved in the retrograde transmission of injury effector molecules and injury-related signals within axons. Demyelinated axons become targets for immune effector molecules and cells, and demyelinated lesions are likely the primary locus for the initiation of a cascade of events that culminate in the loss of the axon and the death of the neuron cell body. However, it is unclear how signals generated distally in the axon, at the site of injury, are transmitted to the neuron cell body where they can engage transcriptional and translational changes necessary for the induction of apoptosis. My lab is applying my previous findings regarding the signaling endosome hypothesis to the analysis and characterization of the retrograde transport of "death endosomes".

Identification of new tools for the prevention of immune-mediated injury to axons and neurons. Based on our observations regarding the role of perforin and perforin-competent effector cells, we are actively engaged in discovering and designing new tools to thwart the function of perforin within the specific context of the demyelinated axon. Likewise, we are currently testing the use of clinically-relevant protease inhibitors in the prevention of neuronal death associated with acute picornaviral infection.