Human Cytomegalovirus - New Exit Pathway Revealed

The group Quantitative Virology headed by Jens Bosse (MHH, LIV, CSSB) has revealed a novel exit pathway used by the Human Cytomegalovirus (HCMV) to spread infection in human cells. The research study, published in PLoS Pathogens, shows that HCMV can release new virus particles in bulk pulses. According to the researchers, this new exit pathway may contribute to the diversity of HCMV particles, explaining the virus’ ability to infect different cell types. 

Viral infections begin when a virus penetrates a host cell and reprograms the host cell to enable the creation of new viral particles. For infection to spread, these new viral particles must find a way to get released and infect the next host cell. A newly produced viral particle's journey to leave the infected cell is known as an egress pathway.

In the one known egress pathway for HCMV, single virus particles are enveloped into small transport vesicles and continuously excreted from the infected cell. “Several studies showed virus particles inside multivesicular structures, but none could link them to an egress pathway,” explains Jens Bosse. “We were intrigued and decided to investigate the spatiotemporal dynamics of these structures in more detail.”

With the help of LIV’s imaging facilities, and using an integrative approach based on volumetric live-cell imaging and three-dimensional correlative light and electron microscopy (3D-CLEM), the researchers could identify accumulations of enveloped virus particles in multivesicular bodies, which they dubbed multi-viral bodies (MViBs). “With live-cell imaging, we were able to demonstrate that these MViBs are transported outwards and subsequently fused with the cellular membrane, releasing large numbers of viral particles at once”, explains the paper’s first author Felix Flomm. “The infected cells are essentially spitting out hundreds of virus particles at once”. The existence of multiple egress pathways could explain the large diversity of HCMV viral particles.

HCMV causes a lifelong latent infection in most healthy individuals; however, in immunocompromised patients and newborns, it can lead to severe disease that affects different tissues and organs. “Understanding HCMV’s egress pathways is essential for developing novel antiviral strategies for this clinically relevant pathogen,” notes Jens Bosse. The researchers will now look into how the bulk release of HCMV particles is triggered within the infected cell.

Image:

3D-live cell lattice light sheet imaging of an HCMV infected cell. Green indicates viral capsids and red viral membranes. Highlighted is one MViB, which is transported to the plasma membrane, where it fuses, releasing its viral cargo.

Publication:

Flomm FJ, Soh TK, Schneider C, Wedemann L, Britt HM, Thalassinos K et al. (2022) Intermittent bulk release of human cytomegalovirus. PLoS Pathogens.

https://doi.org/10.1371/journal.ppat.1010575

The review based on the story: https://pubmed.ncbi.nlm.nih.gov/35607767/

With editorial mention: https://onlinelibrary.wiley.com/doi/10.1111/mmi.14950

And front cover: https://onlinelibrary.wiley.com/doi/10.1111/mmi.14746