ABSTRACT Microsporidia are intracellular pathogens related to the Fungi that have been studied for more than 150 years. They are opportunistic pathogens in patients with AIDS, most commonly causing diarrhea, encephalitis, myositis, or conjunctivitis. In patients with advanced AIDS they have been etiologic in up to 30% of cases of chronic diarrhea with wasting. Microsporidia have also been found to cause infections in other immunocompromised hosts, such as patients who have undergone organ transplantation or those on immune modulating therapies. Infections are now also being recognized in immune competent hosts causing either keratoconjunctivitis or diarrhea. Microsporidia are classified as NIH category B priority pathogens and EPA pathogens of interest as they are transmitted by both food and water sources. In addition to being human pathogens, these pathogenic organisms have major economic impacts on agriculture (via effects on insects and sericulture), aquaculture and animals (food, domestic and wildlife). Infections in animals range from cryptic, benign infections to spectacular, massive infections that cause extensive damage and often death of the host. Microsporidia produce spores containing a unique invasion organelle, the polar tube, which is one of the most complex single celled forms known in the biological world. The mechanism by which the polar tube interacts with its host cell during invasion is still unknown. A long standing research program in my laboratory group is focused on understanding the mechanism of invasion and the structural biology and composition of the polar tube. We have developed techniques for the purification of this structure, identified polar tube proteins (PTPs) and their post translational modifications, and defined methods to study how these proteins interact. Furthermore, our investigations have defined the invasion synapse and the functional role(s) of several PTPs in the process of invasion. However, the full complement of proteins in this structure and the interactions of these components during invasion remain to be determined. This research grant will employ a combination of proteomic, immunologic and ultrastructural studies to characterize the polar tube and its protein interactome to better define and understand the mechanism of invasion. Furthermore, advanced microscopic techniques (i.e. cryo-EM and super resolution microscopy) will be employed to provide insight into the three dimensional structure of the polar tube and arrangement of PTPs providing critical information on fundamental questions concerning the organization of this invasion organelle that have not been able to be resolved by traditional microscopy. In other microbes studies on invasion have provided critical data for understanding pathogenesis and for new therapeutic approaches to the management of infections. We have already demonstrated that antisera to various PTPs can inhibit invasion and infection. We believe that studies of the composition, formation and function of this organelle during germination and invasion should provide a basis for the development of new strategies for control of these important HIV-associated pathogens.
|Effective start/end date||5/16/16 → 4/30/18|
- National Institute of Allergy and Infectious Diseases: $420,000.00
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