# Molecular mechanisms of attachment by the ventral disc in Giardia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $521,438

## Abstract

Giardia is a widespread zoonotic intestinal parasite that causes acute and chronic diarrheal
disease in more than 280 million people each year. Motile trophozoites colonize and attach to
the small intestine with the ventral disc, a complex microtubule organelle. Attachment is
required for infection as it allows Giardia to resist peristalsis. Theoretical models of attachment
must be grounded in accurate biological data. For 50 years, hydrodynamic suction has been
extensively modeled as the leading mechanism for Giardia attachment, yet this model of
attachment lacks empirical support. Our pioneering work on disc architecture and composition,
combined with our development of CRISPR-mediated knockdowns and knockouts and
bioluminescent imaging of infection dynamics in animals, enable us to genetically test the
structural and/or functional roles of DAPs required for disc conformational dynamics in
attachment. During early stages of attachment, we discovered that regions of the disc undergo
specific conformational changes. These changes, along with the presence of a curved disc,
likely create a “seal” that enables attachment to the surface and resistance to shear forces. We
have also recently identified and localized 87 disc-associated proteins (DAPs) to the specific
structural and functional regions of the disc involved in maintaining and modulating disc
conformations. Here we use our new CRISPR-based genetic tools to create specific classes of
DAP mutants associated with key regions of the ventral disc that are likely required for its
domed structure, as well as DAP mutants in key regions associated with flexible movements.
We evaluate structural and attachment defects in CRISPR-interference (CRISPRi) DAP
knockdowns (10 total) using high-resolution live imaging, electron microscopy, and biophysical
assays. In Aim 1, we interrogate the role of the conspicuous microribbon and crossbridge
complexes of the disc in mediating disc curvature. In Aim 2, we define the structural and
functional roles of overlap zone DAPs that may structurally link the upper and lower portions of
the disc, enabling proper domed conformation. In Aim 3, we interrogate the molecular
mechanisms of DAPs associated with disc margin and ventral groove movements that
contribute to formation of the lateral crest seal needed to resist shear forces. Lastly, we evaluate
aberrant infection dynamics of two disc structural mutants using in vivo bioluminescent imaging
(BLI) in an animal model of infection. Therapies that target parasite attachment would limit host
colonization and limit the dissemination of infectious cysts.

## Key facts

- **NIH application ID:** 10552607
- **Project number:** 5R01AI077571-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Scott C Dawson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $521,438
- **Award type:** 5
- **Project period:** 2009-03-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552607

## Citation

> US National Institutes of Health, RePORTER application 10552607, Molecular mechanisms of attachment by the ventral disc in Giardia (5R01AI077571-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10552607. Licensed CC0.

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