using ML to investigate cellular mechanism in infected cell

Using an artificial intelligence (AI) cell classification technique, Northwestern Medicine investigators found that viruses can control structural and genetic polarity inside the cell nucleus. The findings, published in Nature, highlight the importance of genome organization during infection and the extent to which AI can help scientists identify complex intracellular processes.

Viruses can control cells in many ways, from viral proteins present in the nucleus directly controlling gene expression to proteins working on the cell's surface or in the cytoplasm to control cell signaling networks. But how and why the nucleus is moved and reorganized under various conditions, including during viral infection, has remained a matter of investigation, according to the authors.

A core issue in studying any intracellular process is that there's often considerable heterogeneity in what is happening in each individual cell within a cell culture, according to Derek Walsh, Ph.D., professor of Microbiology-Immunology and senior author of the study.

"During infection, for example, you can have some uninfected cells, where some infections fail, and in those that are infected, each cell can be at a different stage of infection. This is very hard to experimentally control or synchronize, and standard approaches such as blotting simply give an 'average' of what is happening at a given time when you harvest cells," Walsh said.

developed automated cell imaging systems that use AI based networks called convolutional neural networks to identify and analyze infected cells.

Specifically, the investigators provided the system large training datasets to learn how to identify infected cells and different stages of infection in the cells. Once the network was trained, the team programmed a microscope to scan and image entire coverslips containing cell cultures. The system then sorted and classified which cells were infected and at what stage of infection they were at.

Using the system, the investigators identified an extensive regulatory pathway from samples of infected cells. This pathway generates strong acetylated microtubules—tubular structures present in the cytoplasm—which attach to the cell's nuclear membrane and intranuclear proteins to control actin filaments. This, in turn, reorganized the cell nucleus internally, controlling its structural and genetic polarity.

"What was surprising was that a virus can form microtubules in the cytoplasm that effectively grab hold of the nuclear surface, and then uses this to reorganize the inside of the nucleus in a form of 'outside-in' control. Another surprising aspect was the discovery that nuclear actin filaments are involved," Walsh said.

The findings, according to Walsh, may improve the understanding of the fundamental mechanisms of genome organization in infected cells and how this contributes to overall infection.

 

reference

Cytoplasmic control of intranuclear polarity by human cytomegalovirus. Nature (2020). doi.org/10.1038/s41586-020-2714-x