Scientists would like to unlock the secrets of bacteriophages’ evolutionary strategies in their ongoing conflict with bacteria. Now, a group of researchers from the University of California, San Diego (UCSD), report new insights into previously unrecognized phage biological structures and processes.
Their findings are published in the journal Nature in a paper titled, “Architecture and self-assembly of the jumbo bacteriophage nuclear shell,” which offers an unprecedented look into “jumbo phages” and their evolved defenses against bacteria.
“Bacteria encode myriad defenses that target the genomes of infecting bacteriophage, including restriction–modification and CRISPR–Cas systems,” wrote the researchers. “In response, one family of large bacteriophages uses a nucleus-like compartment to protect its replicating genomes by excluding host defense factors. However, the principal composition and structure of this compartment remain unknown. Here we find that the bacteriophage nuclear shell assembles primarily from one protein, which we name chimallin (ChmA).”
The research team characterized the structure of the nucleus-like compartment for the first time using cryo-electron microscopy and tomography at the highest resolution possible for cell imaging.
“It’s a different kind of compartment—unlike anything we have ever seen in nature,” said Elizabeth Villa, PhD, an associate professor in the UCSD School of Biological Sciences and a Howard Hughes Medical Institute investigator. “We were able to characterize this compartment—how it assembles and functions at the most basic level—from each atom to the scale of the entire organism.”
The researchers found that the compartment allows certain key components inside, while simultaneously serving as a defense mechanism against bacterial threats.
“These discoveries present us with a whole new era of phage biology,” said Villa. “The shell serves as a growing shield for protection but it also has to import and export some things, and it does this with exquisite precision and selectivity. It’s really weird biology.”
Study co-author Joe Pogliano, PhD, professor of biological sciences at UCSD, believes nucleus-forming phages could be better for phage therapies against bacterial infections because they evolved to be naturally resistant to many types of bacterial defense systems.
“As we move toward the development of phage therapies, we’ll need to learn more about this newly discovered phage nucleus since it appears to make them better at attacking bacteria,” said Pogliano.
Researchers, including Pogliano and Villa, will be collaborating with others in UCSD’s Center for Innovative Phage Applications and Therapeutics, the first dedicated phage therapy center in North America.
“Now that we know certain phages have a shield, we could give it to other phages and make ‘super phages’ that are better at phage therapy and overcoming bacterial defenses. The first step in that process is understanding the structure of the chimallin protein which makes up the shield, which is one reason this work is so important.”
Kevin Corbett, PhD, professor, department of cellular and molecular medicine, UCSD, added biochemistry and structural biology expertise to the research team. He described the findings as an example of convergent evolution in which distantly related organisms find similar ways to solve problems.
“The nuclear pore in eukaryotes is a gigantic, complex structure with very distinctive ways of keeping most proteins out but specifically importing others. What we’re probably looking at with the jumbo phage is a dramatically simpler method of solving the same problem,” explained Corbett. “It’s an amazingly creative solution—similar but simpler—to protecting its genome from the outside world by building a wall to separate it from bacterial defenses.”
“We now know the principle structure of the compartment of a mature phage nucleus, but we’d like to know how it assembles to begin with,” added co-first author Thomas Laughlin, PhD, a biological sciences postdoctoral scholar. “What is the biogenesis (or ‘prequel’) at the early stages of infection? How does it all start once the virus injects its genome into the host bacteria?” Laughlin asked. These findings set the stage for future identification of minor shell components that manage shell nucleation and growth and may help answer these questions.