From Cells to Atoms: Cryo-EM as an Essential Tool to Investigate Pathogen Biology, Host-Pathogen Interaction and Drug Discovery.

Shepherd, Doulin C; Dalvi, Somavally; Ghosal, Debnath

Electron cryo-microscopy (cryo-EM) has lately emerged as a powerful method in structural biology and cell biology. While cryo-EM single-particle analysis (SPA) is now routinely delivering structures of purified proteins and protein complexes at near-atomic resolution, the use of electron cryo-tomography (cryo-ET), together with subtomogram averaging, is allowing visualization of macromolecular complexes in their native cellular environment, at unprecedented resolution. The unique ability of cryo-EM to provide information at many spatial resolution scales from ångströms to microns makes it an invaluable tool that bridges the classic 'resolution-gap' between structural biology and cell biology domains. Like in many other fields of biology, in recent years, cryo-EM has revolutionized our understanding of pathogen biology, host-pathogen interaction and has made significant strides towards structure-based drug discovery. In a very recent example, during this ongoing coronavirus disease (COVID-19) pandemic, the structure of the stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein was deciphered by SPA. This led to the development of multiple vaccines. Alongside, cryo-ET provided key insights into the structure of the native virion, mechanism of its entry, replication, and budding; demonstrating the unrivaled power of cryo-EM in investigating pathogen biology, host-pathogen interaction and drug discovery. In this review, we showcase a few examples of how different imaging modalities within cryo-EM have enabled the study of microbiology and host-pathogen interaction.