Microsporidia are intracellular pathogens transmitted by food and water that cause infection in patients with AIDS. They infect cells using a unique specialized invasion organelle, the polar tube. Infection occurs in the gastrointestinal, ocular, reproductive, respiratory, muscle, excretory and nervous systems. The approximately 200 genera and 1800 species of Microsporidia parasitize a wide range of invertebrate and vertebrate hosts, including humans. They are important parasites in HIV and other immune-compromised patients, and can also infect immune-competent humans as well as insects, fish, mammals and birds.
Using a combination of proteomic and cell biology approaches, the laboratory of Louis M. Weiss MD, MPH is investigating the function and composition of the polar tube, spore coat and polaroplast, which make up the invasion organelle of these pathogens. Despite its description as a morphologic structure over 100 years ago, the full complement and interactions of the proteins making up this structure, the mechanism of its formation during invasion, and the cell biology underlying its formation are still not understood. Dr. Weiss and his team aim to define the invasion organelle, its proteome and interactome. Their goal: to provide new insights into the polar tube’s structure, dynamics and organization and shed light on the mechanism(s) of host cell invasion by these organisms.
The morbidity and overall disease burden associated with microsporidiosis can be significant; for example, microsporidian diarrhea in the AIDS patients is associated with a significant increase in mortality.
Methionine aminopeptidase type 2 (MetAP2) is a highly validated target for treatment of microsporidiosis. Microsporidia lack MetAP1, making MetAP2 an essential enzyme for the microsporidia. Among eukaryotes this makes them highly susceptible to MetAP2 inhibitors and limits the toxicity of these compounds in their hosts. Use of fumagillin and its derivatives, which covalently bind to and inhibit MetAP2 (but not MetAP1), has confirmed that inhibition of MetAP2 is an effective in vitro and in vivo therapeutic target for many species of microsporidia. The Weiss Laboratory has cloned, expressed and determined the crystal structure of the microsporidian Encephalitozoon cuniculi MetAP2 (i.e. EcMetAP2) and has developed Saccharomyces cerevisiae dependent on Ec MetAP2 for growth. In collaboration with Dr. Bhaskar Das at Mount Sinai they are developing (using a Limited Rational Design approach) and testing new competetive inhibitors of MetAP2 with increased selectivity for microsporidia.