Abstract
During infection with positive-strand RNA viruses, viral RNA synthesis associates with modified intracellular membranes that form unique and captivating structures in the cytoplasm of the infected cell. These viral replication organelles (ROs) play a key role in the replicative cycle of important human pathogens like coronaviruses, enteroviruses, or flaviviruses. From their discovery to date, progress in our understanding of viral ROs has closely followed new developments in electron microscopy (EM). This review gives a chronological account of this progress and an introduction to the different EM techniques that enabled it. With an ample repertoire of imaging modalities, EM is nowadays a versatile technique that provides structural and functional information at a wide range of scales. Together with well-established approaches like electron tomography or labeling methods, we examine more recent developments, such as volume scanning electron microscopy (SEM) and in situ cryotomography, which are only beginning to be applied to the study of viral ROs. We also highlight the first cryotomography analyses of viral ROs, which have led to the discovery of macromolecular complexes that may serve as RO channels that control the export of newly-made viral RNA. These studies are key first steps towards elucidating the macromolecular complexity of viral ROs.
Highlights
The histories of electron microscopy (EM) and virus research have been closely intertwined since the invention of the electron microscope almost a century ago [1,2]
For electrontomography, the specimen is gradually tilted in a transmission EM (TEM) to generate a so-called tilt series that consists of 2D projection images of the specimen at different angles
These results suggest that the virus-induced membrane structures accommodate viral RNA synthesis, serving as viral replication organelles (ROs)
Summary
The histories of electron microscopy (EM) and virus research have been closely intertwined since the invention of the electron microscope almost a century ago [1,2]. For electron (cryo)tomography, the specimen is gradually tilted in a TEM to generate a so-called tilt series that consists of 2D projection images of the specimen at different angles. These projections are computationally aligned and combined into a tomographic volume. Viruses as relevant and diverse as coronaviruses, enteroviruses, or flaviviruses drastically remodel the cellular landscape transforming intracellular membranes into distinct structures that support the synthesis of viral RNA These virus-induced membrane structures have received many names in the literature, from viral factories to replication complexes, but perhaps the term replication organelle (RO) best conveys the idea of a subcellular structure that serves a specific function. Many questions about the biogenesis and function of viral ROs remain open, significant progress has been made in the last decades, often going hand in hand with new developments in the field of EM
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