Giardiasis is the most common cause of acute protozoan intestinal infection worldwide, and chronic giardiasis is a major contributor to high morbidity in developing countries. Due to the lack of concerted research efforts, giardiasis has been designated a World Health Organization (WHO) neglected disease. Giardia intestinalis is a parasitic protist, and its pathogenicity is dependent upon attachment to the intestinal microvilli via the ventral disc, a novel cytoskeletal structure. Conflicting biophysical support and a conspicuous lack of molecular evidence have hampered the investigation of proposed giardial attachment mechanisms. The primary focus here is to evaluate support for two """"""""classic"""""""" hypotheses that explain giardial attachment: the """"""""Conformational Change"""""""" model and the """"""""Hydrodynamic"""""""" model. The """"""""Conformational Change"""""""" model proposes that conformational changes of the ventral disc cause suction-based attachment. We will investigate putative disc conformational dynamics using high resolution cryoelectron tomography of the ventral disc, live cell imaging, and novel attachment assays (Aim 1). We will also examine the role of disc-associated annexins (1-giardins) in disc conformational dynamics (Aim 2), and identify and characterize novel disc-associated components using a genome-wide, high-throughput random GFP visual screen (Aim 3). The """"""""Hydrodynamic Model"""""""" of giardial attachment posits that the ventral flagella produce a hydrodynamic current enabling suction-based attachment. To test this alternative, we will assay attachment dynamics in various mutants with motility defects (Aim 2). Lastly, to inform our analyses of disc structure and function (Aims 1-3), we will characterize dorsal disc biogenesis and parental disc disassembly during cell division (Aim 4). After mitosis, two dorsal daughter discs are assembled and the parental ventral disc and median body are disassembled. Using live imaging of photoactivatable GFP- tagged strains and analyses of microtubule disassembly mutants, we will test the hypothesis that the median body acts as a reservoir of disc components for dorsal daughter discs.

Public Health Relevance

Giardia intestinalis is one of the ten major parasites in humans, and the current lack of understanding about Giardia has resulted in it being designated a """"""""neglected disease"""""""". One sixth of the world's population is believed to suffer from giardiasis. Giardia attaches to the host small intestine via an undefined mechanism. The research proposed here directly investigates the attachment mechanism of Giardia, and will offer additional targets for drug discovery. Specifically we investigate the function of the """"""""ventral disc"""""""" a suction cup-like structure.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Barash, N R; Maloney, J G; Singer, S M et al. (2017) Giardia Alters Commensal Microbial Diversity throughout the Murine Gut. Infect Immun 85:
Pham, Jonathan K; Nosala, Christopher; Scott, Erica Y et al. (2017) Transcriptomic Profiling of High-Density Giardia Foci Encysting in the Murine Proximal Intestine. Front Cell Infect Microbiol 7:227
McInally, Shane G; Dawson, Scott C (2016) Eight unique basal bodies in the multi-flagellated diplomonad Giardia lamblia. Cilia 5:21
Brown, Joanna R; Schwartz, Cindi L; Heumann, John M et al. (2016) A detailed look at the cytoskeletal architecture of the Giardia lamblia ventral disc. J Struct Biol 194:38-48
Nosala, Christopher; Dawson, Scott C (2015) The Critical Role of the Cytoskeleton in the Pathogenesis of Giardia. Curr Clin Microbiol Rep 2:155-162
Vicente, Juan-Jesus; Cande, W Zacheus (2014) Mad2, Bub3, and Mps1 regulate chromosome segregation and mitotic synchrony in Giardia intestinalis, a binucleate protist lacking an anaphase-promoting complex. Mol Biol Cell 25:2774-87
Dawson, Scott C; Paredez, Alexander R (2013) Alternative cytoskeletal landscapes: cytoskeletal novelty and evolution in basal excavate protists. Curr Opin Cell Biol 25:134-41
Wilson, Katherine L; Dawson, Scott C (2011) Evolution: functional evolution of nuclear structure. J Cell Biol 195:171-81
Hirst, Marissa B; Kita, Kelley N; Dawson, Scott C (2011) Uncultivated microbial eukaryotic diversity: a method to link ssu rRNA gene sequences with morphology. PLoS One 6:e28158
Hagen, Kari D; Hirakawa, Matthew P; House, Susan A et al. (2011) Novel structural components of the ventral disc and lateral crest in Giardia intestinalis. PLoS Negl Trop Dis 5:e1442

Showing the most recent 10 out of 15 publications