Multistep entry of rotavirus into cells: a Versaillesque dance

https://doi.org/10.1016/j.tim.2004.04.003Get rights and content

Abstract

Rotavirus entry into a cell is a complex multistep process in which different domains of the rotavirus surface proteins interact with different cell surface molecules, which act as attachment and entry receptors. These recently described molecules include several integrins and a heat shock protein, which have been found to be associated with cell membrane lipid microdomains. The requirement during viral entry for several cell molecules, which might be required to be present and organized in a precise fashion, could explain the selective cell and tissue tropism of these viruses. This review focuses on recent data describing the virus–receptor interactions, the role of lipid microdomains in rotavirus infection and the mechanism of rotavirus cell entry.

Section snippets

Rotaviruses

Rotaviruses are the leading etiologic agent of severe diarrheal disease in infants and young children worldwide, being responsible for an estimated 500 000 deaths each year [10]; therefore, there is an urgent need to develop effective vaccination and therapeutic strategies to combat these viruses. Fundamental for these developments is a thorough basic understanding of the molecular mechanisms that rotaviruses use to interact with their host cell and replicate.

Rotavirus particles consist of

Rotavirus receptors

It is generally accepted that N-acetylneuraminic acid, also known as sialic acid (SA), is required by some animal rotavirus strains to attach to the cell surface. The infectivity of these strains is greatly diminished by the treatment of cells with neuraminidase (NA); consequently, these strains are NA-sensitive. By contrast, many animal strains and most strains isolated from humans are NA-resistant [15]; however, this does not mean that these strains do not use SA for cell attachment because

Virus–receptor interactions

Several lines of evidence suggest that rotaviruses interact sequentially with several cell surface molecules to enter the cell, using different domains of the virus surface proteins VP4 and VP7 during this process 12, 21, 23, 24, 25, 26, 27, 28, 29, 30. This evidence has been obtained through: (i) a rotavirus competition infection assay that detects virus competition at both binding and post-binding steps [28]; (ii) the characterization of a mutant virus that binds to the cell surface with a

Role of lipid rafts in virus cell entry

The infectivity of rotaviruses is partially blocked by metabolic inhibitors of N-glycosylation and glycolipid synthesis, and is also severely impaired by the depletion of cholesterol from the cellular membrane [43]. On the basis of these findings it was suggested that sphingolipid- and cholesterol-enriched membrane lipid microdomains, usually referred to as lipid rafts (Box 2) [44], might be involved in the entry of rotaviruses into the cell 27, 43, 45. The participation of lipid rafts in

Mechanism of rotavirus cell entry

Early electron microscopy studies of rotavirus-infected cells suggested endocytosis as the virus internalization pathway. However, it was later shown that rotavirus infectivity is not inhibited either by preventing the acidification of endosomes or by drugs that block the intracellular traffic of endocytic vesicles [9]. Direct cell membrane penetration has also been postulated as the mechanism of virus entry on the basis of electron microscopy data and on the observation that rotavirus

Concluding remarks

The recent advances in understanding the early interactions of rotavirus with its host cell have been fueled by the identification of rotavirus cell receptors. Progress in understanding plasma membrane organization, the definition of different types of endocytosis and the application of cryo-electron microscopy to study virus structure, have also been crucial for this purpose. The data presented here indicate the existence of several rotavirus receptors, some of which interact sequentially with

Acknowledgements

We would like to thank U. Desselberger for critical reading of the manuscript and for valuable suggestions and comments, and also P. Isa and E. Méndez for helpful discussions on the manuscript. We appreciate the support by B.V.V. Prasad for providing the cryo-electron microscopy images of the virus. We apologize to colleagues whose work has not have been cited in full owing to length constraints. Work on rotavirus cell entry in our laboratories is supported by grants 55003662 and 55000613 from

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