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Giant Bacteriophages Bridge Gap between Living Microbes and Viral Machines

Bacteriophages — viruses that infect bacteria — are considered distinct from cellular life owing to their inability to carry out most biological processes required for reproduction. Typically, they have small genomes and depend on their bacterial hosts for replication. Now, an international team of scientists has discovered 351 new species of bacteriophages with giant genomes and capabilities normally associated with living organisms, blurring the line between living microbes and viral machines.

Depiction of huge bacteriophages (red, left) and normal phages infecting a bacterial cell. The huge phage injects its DNA into the host cell, where Cas proteins -- part of the CRISPR immune system typically found only in bacteria and archaea -- manipulate the host cell’s response to other viruses. The authors have not yet photographed any huge phages, so all are depicted resembling the most common type of phage, T4. Image credit: Jill Banfield Lab / University of California, Berkeley.

Depiction of huge bacteriophages (red, left) and normal phages infecting a bacterial cell. The huge phage injects its DNA into the host cell, where Cas proteins — part of the CRISPR immune system typically found only in bacteria and archaea — manipulate the host cell’s response to other viruses. The authors have not yet photographed any huge phages, so all are depicted resembling the most common type of phage, T4. Image credit: Jill Banfield Lab / University of California, Berkeley.

University of California, Berkeley’s Professor Jill Banfield and colleagues from the U.S., Denmark, Japan, Canada, China, South Africa, France, the UK and Australia found huge bacteriophages by scouring a large database of DNA that they generated from nearly 30 different Earth environments, ranging from the guts of premature infants and pregnant women to a Tibetan hot spring, a South African bioreactor, hospital rooms, oceans, lakes and deep underground.

“We are exploring Earth’s microbiomes, and sometimes unexpected things turn up. These viruses of bacteria are a part of biology, of replicating entities, that we know very little about,” Professor Banfield said.

“These huge phages bridge the gap between non-living bacteriophages, on the one hand, and bacteria and Archaea. There definitely seem to be successful strategies of existence that are hybrids between what we think of as traditional viruses and traditional living organisms.”

The researchers identified 351 bacteriophages with genomes that were more than 200,000 bases long, four times the average phage genome length of 50,000 bases.

Among these is the largest bacteriophage discovered to date — its genome, 735,000 base-pairs long, is nearly 15 times larger than the average phage. This largest known phage genome is much larger than the genomes of many bacteria.

While most of the genes in these huge phages code for unknown proteins, the scientists were able to identify genes that code for proteins critical to the machinery, called the ribosome, that translates messenger RNA into protein. Such genes are not typically found in viruses, only in bacteria or Archaea.

The study authors found many genes for transfer RNAs (tRNAs), which carry amino acids to the ribosome to be incorporated into new proteins; genes for proteins that load and regulate tRNAs; genes for proteins that turn on translation and even pieces of the ribosome itself.

“Typically, what separates life from non-life is to have ribosomes and the ability to do translation; that is one of the major defining features that separate viruses and bacteria, non-life and life,” said Dr. Rohan Sachdeva, a researcher in the Innovative Genomics Institute at the University of California, Berkeley.

“Some large phages have a lot of this translational machinery, so they are blurring the line a bit.”

Giant bacteriophages likely use these genes to redirect the ribosomes to make more copies of their own proteins at the expense of bacterial proteins. Some huge phages also have alternative genetic codes, the nucleic acid triplets that code for a specific amino acid, which could confuse the bacterial ribosome that decodes RNA.

One of the newly-discovered giant phages is able to make a protein analogous to the Cas9 protein that is part of the revolutionary gene-editing tool CRISPR-Cas9.

The team dubbed this protein CasØ, because the Greek letter Ø (phi) has traditionally been used to denote bacteriophage.

“It is fascinating how these phages have repurposed this system we thought of as bacterial or archaeal to use for their own benefit against their competition, to fuel warfare between these viruses,” said Basem Al-Shayeb, a graduate student at the University of California, Berkeley.

“In these huge phages, there is a lot of potential for finding new tools for genome engineering,” Dr. Sachdeva said.

“A lot of the genes we found are unknown, they don’t have a putative function and may be a source of new proteins for industrial, medical or agricultural applications.”

“The high-level conclusion is that phages with large genomes are quite prominent across Earth’s ecosystems, they are not a peculiarity of one ecosystem,” Professor Banfield said.

“And phages which have large genomes are related, which means that these are established lineages with a long history of large genome size.”

“Having large genomes is one successful strategy for existence, and a strategy we know very little about.”

The research is described in a paper in the journal Nature.

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B. Al-Shayeb et al. Clades of huge phages from across Earth’s ecosystems. Nature, published online February 12, 2020; doi: 10.1038/s41586-020-2007-4

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