The primary goal of this project is to understand how microsporidia cause disease. Microsporidia are eukaryotic intracellular pathogens that can infect a wide variety of hosts but are poorly understood. These pathogens can cause serious infections in humans, particularly in AIDS patients. Understanding the pathogenic properties of microsporidia is relevant to the NIH's mission because it promises to help reduce the burden of human illness. Very little is known about the molecular interactions between microsporidia and their host intestinal cells, although several observations suggest that there is an intimate dynamic between them. Our long-term goal is to better understand the strategies that microsporidia use to exploit host intestinal cells, as well as the strategies hosts use to control these infections. The objective of this proposal is to investigate the molecular interactions between the nematode C. elegans and its natural microsporidian pathogen, N. parisii. N. parisii infects C. elegans intestinal cells, which are transparent, facilitating direct imaging of the infection. C. elegans intestinal cells share many features with mammalian intestinal cells, such as finger-like microvilli, which are anchored into a cytoskeletal structure called the terminal web. Intriguingly, N. parisii can specifically manipulate the terminal web, probably as part of an exit strategy. The central hypothesis of this proposal is that there are specific molecular interactions between host and pathogen that allow N. parisii to directly target host cell components, and that allow C. elegans to regulate resistance to infection. We will pursue two specific aims to address this hypothesis: 1) determine the mechanisms used by N. parisii to restructure and modify C. elegans intestinal cells;and 2) identify the pathways that are important for regulating resistance/susceptibility to N. parisii infection. To accomplish the first aim we will use in vivo imaging of N. parisii infection in animals expressing fluorescently-labeled cytoskeletal and subcellular markers in the C. elegans intestine. These studies will be complemented with physiological and biochemical analyses of the consequences of infection. Under the second aim we will use a combination of genetic and genomic techniques to identify which pathways are important for control of N. parisii infection. The approach is innovative because it utilizes a natural host/pathogen model that offers genetic, molecular, and imaging tools to better understand molecular interactions between microsporidia and their hosts. The proposed research is significant because it is expected to provide insights into the molecular interactions between microsporidia and their human hosts.

Public Health Relevance

Microsporidia are responsible for a wide variety of infections, including severe intestinal infections in AIDS patients. However, the molecular mechanisms used by microsporidia to infect host cells, and the host innate immune response to these infections, are poorly understood. This proposal employs a natural nematode host model for microsporidia pathogenesis in the intestine that has potential applicability to understanding the pathogenesis of microsporidian infections in the human intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087528-03
Application #
8204946
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2010-01-15
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Szumowski, Suzannah C; Estes, Kathleen A; Popovich, John J et al. (2016) Small GTPases promote actin coat formation on microsporidian pathogens traversing the apical membrane of Caenorhabditis elegans intestinal cells. Cell Microbiol 18:30-45
Reddy, Kirthi C; Dunbar, Tiffany L; Nargund, Amrita M et al. (2016) The C. elegans CCAAT-Enhancer-Binding Protein Gamma Is Required for Surveillance Immunity. Cell Rep 14:1581-9
Balla, Keir M; Andersen, Erik C; Kruglyak, Leonid et al. (2015) A wild C. elegans strain has enhanced epithelial immunity to a natural microsporidian parasite. PLoS Pathog 11:e1004583
Luallen, Robert J; Bakowski, Malina A; Troemel, Emily R (2015) Characterization of microsporidia-induced developmental arrest and a transmembrane leucine-rich repeat protein in Caenorhabditis elegans. PLoS One 10:e0124065
Cohen, Lianne B; Troemel, Emily R (2015) Microbial pathogenesis and host defense in the nematode C. elegans. Curr Opin Microbiol 23:94-101
Reinke, Aaron W; Troemel, Emily R (2015) The Development of Genetic Modification Techniques in Intracellular Parasites and Potential Applications to Microsporidia. PLoS Pathog 11:e1005283
Troemel, Emily R; Becnel, James J (2015) Genome analysis and polar tube firing dynamics of mosquito-infecting microsporidia. Fungal Genet Biol 83:41-4
Szumowski, Suzannah C; Troemel, Emily R (2015) Microsporidia-host interactions. Curr Opin Microbiol 26:10-6
Bakowski, Malina A; Priest, Margaret; Young, Sarah et al. (2014) Genome Sequence of the Microsporidian Species Nematocida sp1 Strain ERTm6 (ATCC PRA-372). Genome Announc 2:
Szumowski, Suzannah C; Botts, Michael R; Popovich, John J et al. (2014) The small GTPase RAB-11 directs polarized exocytosis of the intracellular pathogen N. parisii for fecal-oral transmission from C. elegans. Proc Natl Acad Sci U S A 111:8215-20

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