From cells to atoms: Cryo‐EM as an essential tool to investigate pathogen biology, host–pathogen interaction, and drug discovery

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 toward structure‐based drug discovery. In a very recent example, during the 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. Electron cryo‐microscopy (cryo‐EM) is unique in its ability to image biological samples across scales, from cells to molecules. While cryo‐EM single‐particle analysis (SPA) provides near‐atomic resolution information of purified proteins and protein complexes, the use of electron cryo‐tomography (cryo‐ET) allows visualization of cellular landscapes and protein complexes in situ, in unprecedented detail. Like in many other fields of biology, cryo‐EM is revolutionizing our understanding of pathogen biology, host–pathogen interaction and making significant strides towards structure‐based drug/vaccine development.