James J. Pestka, Ph.D.

pestka@msu.edu

Research

1. Molecular mechanisms of trichothecene toxicity:  Trichothecenes are  a novel class of natural toxins produced by fungi in food and the environment that can both induce and suppress inflammatory gene expression thereby disrupting immune function. These compounds bind to eukaryotic ribosomes and initiate a stress response involving activation of protein kinases. We are studying the molecular linkages between the ribosome and these stress-related kinases as well as their relation to downstream gene regulation and apoptosis.  These studies will have relevance to other ribotoxic agents such as ricin and shiga toxin.

2. Xenobiotic suppression of viral-induced mucosal immune responses: Reoviruses induce a robust self-limiting immune response in both the gut and respiratory tract that involve humoral and cell-mediated arms of the immune system. We are using reovirus as a model to study mechanisms by which trichothecene mycotoxins and other xenobiotics disrupt mucosal immune function and thereby suppress viral clearance and exacerbate viral shedding. Data from these studies will provide insight into the role of chemical exposure in increasing sensitivity of viral infection.

3. Omega-3 fatty acid suppression of experiemental IgA nephropathy (IgAN): Consumption of the trichothecene deoxynivalenol aberrantly induces  upregulation of IgA production in the mouse that mimics human IgAN, the most type of glomerulonephritis worldwide.  Dietary supplementation with omega-3 fatty acids found in fish oil has been shown to have benefits to patients with this disease but the mechanism is unknown. We are studying how  omega-3s suppress protein kinase activation and downstream inflammatory cytokines involved in our IgAN model.  The results will have broad implications for use of these  supplements by an estimated 26 million U.S. adults - largely for prevention of inflammation

4. Upper respiratory tract targets of black mold trichothecenes: The black mold Stachybotrys chartarum frequently occurs in water-damaged buildings and has been associated with illnesses associated with respiratory tract inflammation, immune dysfunction, and  neurocognitive problems.  We have determined that, at very low concentrations, macrocylic trichothecenes produced by this mold can induce both program cell death in olfactory sensory neurons and a robust inflammatory response in  the mouse nasal compartment. We are studying mechanistic basis for these effects and relating this to dose, chronic exposure and interaction with  airborne inflammagens such as endotoxin.  These studies will impact risk assessment and management strategies of this environmental agent.