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
Cohen, Lianne B; Troemel, Emily R (2015) Microbial pathogenesis and host defense in the nematode C. elegans. Curr Opin Microbiol 23:94-101
Bakowski, Malina A; Desjardins, Christopher A; Smelkinson, Margery G et al. (2014) Ubiquitin-mediated response to microsporidia and virus infection in C. elegans. PLoS Pathog 10:e1004200
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
Balla, Keir M; Troemel, Emily R (2013) Caenorhabditis elegans as a model for intracellular pathogen infection. Cell Microbiol 15:1313-22
Dunbar, Tiffany L; Yan, Zhi; Balla, Keir M et al. (2012) C. elegans detects pathogen-induced translational inhibition to activate immune signaling. Cell Host Microbe 11:375-86
Estes, Kathleen A; Szumowski, Suzannah C; Troemel, Emily R (2011) Non-lytic, actin-based exit of intracellular parasites from C. elegans intestinal cells. PLoS Pathog 7:e1002227