Viruses are among the best-known and studied pathogens and infect virtually every living organism from bacteria to humans. As viruses are parasites of their hosts, the life cycle of any virus is inextricably tied to that of the host cell Despite this dependence, all viruses share a number of essential tasks that they must accomplish for survival. Most viruses must find and recognize a cell in which they can replicate, release their genome, generate new viral components and assemble them into precursors that mature into stable, progeny virions that are primed to be transmitted and infect a new host. These tasks are accomplished by viruses in different ways as a result of adaptation to different cellular environments. Each task involves interactions between components within the context of the whole virion and hence requires the visualization of the entire structure at which the techniques of cryo-transmission electron microscopy (cryoEM), cryo-electron tomography (cryoET), and three-dimensional (3D) image reconstruction ('cryo-reconstruction') excel. We will exploit these powerful tools to study a diverse set of viruses, including those that infect humans and other mammals, protozoa, insects, bacteria, and fungi. Numerous projects funded by the current grant have illustrated the structural response of different viruses to the common tasks of the viral life cycle. This proposal involves ongoing as well as new studies that focus on structural investigations of viruses and virus complexes and dynamic events that lie beyond the current realm of crystallographic technology. The large number and extent of our studies are made possible through several fruitful collaborations, which provide important correlative information such as from biochemical, genetic, and X-ray crystallographic experiments. Icosahedral and non-icosahedral and enveloped and non-enveloped viruses will be studied. These include representatives of several different virus families, all of which make excellent model systems for studying form and function: Iridoviridae, Papillomaviridae, Partitiviridae, Parvoviridae, Podoviridae, Siphoviridae, Tetraviridae, Togaviridae, and Totiviridae (and also some yet unclassified viruses). Specific examples include: three totiviruses and one partitivirus that infect protozoa, which in turn cause human disease (Tricomoniasis, Leishmaniasis, Giardiasis, and Cryptosporidiosis);several adeno-associated viruses being developed as gene delivery vectors;Sindbis virus, a BSL-2 select agent;recombinant, virus-like particles of several human papillomavirus serotypes, which together cause >90% of cervical cancers;Sf6 bacteriophage, which infects Shigella flexneri that causes bacillary dysentery in humans;and many other insect and fungal viruses, including one that targets a fungus that infects plants and also causes human allergies. Lastly, the use of bacteriophage P22 capsids and polyheads as nano-particles for drug delivery will be investigated.

Public Health Relevance

Knowledge of virus structure provides critical insights about how viruses and their genomes enter cells, and how they replicate, assemble, mature, and cause disease. High-resolution three-dimensional models of many viruses can be generated from images recorded in transmission electron microscopes followed by computer-based image analysis. The goal of this project is to examine the structures and functions of viruses from many different families, including those that infect humans (alpha-, papilloma-, and parvo- viruses), amphibians (frog virus 3), protozoa (toti- and partiti-viruses), insects (alpha-, irido-,and tetra- viruses), fungi (toti- and partiti-viruses), and bacteria (podo- and sipho-viruses).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM033050-32
Application #
8762186
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Flicker, Paula F
Project Start
1983-06-01
Project End
2018-05-31
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
32
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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