Scientists have discovered hundreds of unusually large, bacteria-killing
viruses with capabilities normally associated with living organisms, blurring
the line between living microbes and viral machines.
These phages —
short for bacteriophages, so-called because they “eat” bacteria — are of a size
and complexity considered typical of life, carry numerous genes normally found
in bacteria and use these genes against their bacterial hosts.
University of
California, Berkeley, researchers and their collaborators found these huge
phages 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.
Altogether they
identified 351 different huge phages, all with genomes four or more times
larger than the average genomes of viruses that prey on single-celled bacteria.
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.
“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,” said Jill Banfield, a UC Berkeley
professor of earth and planetary science and of environmental science, policy
and management, and senior author of a paper about the findings appearing Feb
12 in the journal Nature. “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.”
Ironically,
within the DNA that these huge phages lug around are parts of the CRISPR system
that bacteria use to fight viruses. It’s likely that once these phages inject
their DNA into bacteria, the viral CRISPR system augments the CRISPR system of
the host bacteria, probably mostly to target other viruses.
“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 UC Berkeley graduate
student Basem Al-Shayeb. Al-Shayeb and research associate Rohan Sachdeva are
co-first authors of the Nature paper.
New Cas protein
One of the huge
phages also is able to make a protein analogous to the Cas9 protein that is
part of the revolutionary tool CRISPR-Cas9 that Jennifer Doudna of UC Berkeley
and her European colleague, Emmanuelle Charpentier, adapted for gene-editing.
The team dubbed this tiny protein CasΦ,
because the Greek letter Φ, or
phi, has traditionally been used to denote bacteriophage.
“In these huge
phages, there is a lot of potential for finding new tools for genome
engineering,” 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.”
Aside from
providing new insight into the constant warfare between phages and bacteria,
the new findings also have implications for human disease. Viruses, in general,
carry genes between cells, including genes that confer resistance to
antibiotics. And since phages occur wherever bacteria and Archaea live,
including the human gut microbiome, they can carry damaging genes into the
bacteria that colonize humans.
“Some diseases
are caused indirectly by phages, because phages move around genes involved in
pathogenesis and antibiotic resistance,” said Banfield, who is also director of
microbial research at the Innovative Genomics Institute (IGI) and a CZ Biohub
investigator. “And the larger the genome, the larger the capacity you have to
move around those sorts of genes, and the higher the probability that you will
be able to deliver undesirable genes to bacteria in human microbiomes.”
Sequencing Earth’s biomes
For more than 15
years, Banfield has been exploring the diversity of bacteria, Archaea — which,
she says, are fascinating cousins of bacteria — and phages in different
environments around the planet. She does this by sequencing all the DNA in a
sample and then piecing the fragments together to assemble draft genomes or, in
some cases, fully curated genomes of never-before-seen microbes.
In the process,
she has found that many of the new microbes have extremely tiny genomes,
seemingly insufficient to sustain independent life. Instead, they appear to
depend on other bacteria and archaea to survive.
One year ago,
she reported that some of the largest phages, a group she called Lak phages,
can be found in our guts and mouths, where they prey on gut and saliva
microbiomes.
The new Nature paper came out of a more thorough search
for huge phages within all the metagenomic sequences Banfield has accumulated,
plus new metagenomes provided by research collaborators around the globe. The
metagenomes came from baboons, pigs, Alaskan moose, soil samples, oceans,
rivers, lakes and groundwater, and included Bangladeshis who had been drinking
arsenic-tainted water.
The team
identified 351 phage genomes that were more than 200 kilobases long, four times
the average phage genome length of 50 kilobytes (kb). They were able to
establish the exact length of 175 phage genomes; the others could be much
larger than 200 kb. One of the complete genomes, 735,000 base-pairs long, is
now the largest known phage genome.
While most of
the genes in these huge phages code for unknown proteins, the researchers 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 researchers
found many genes for transfer RNAs, 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,” Sachdeva said. “Some large phages have a lot
of this translational machinery, so they are blurring the line a bit.”
Huge phages
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.
In addition,
some of the newly discovered huge phages carry genes for variants of the Cas
proteins found in a variety of bacterial CRISPR systems, such as the Cas9,
Cas12, CasX and CasY families. CasΦ is a
variant of the Cas12 family. Some of the huge phages also have CRISPR arrays,
which are areas of the bacterial genome where snippets of viral DNA are stored
for future reference, allowing bacteria to recognize returning phages and to mobilize
their Cas proteins to target and cut them up.
“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,” 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 researchers
divided the 351 megaphages into 10 new groups, or clades, named after words for
“big” in the languages of the paper’s co-authors: Mahaphage (Sanskrit),
Kabirphage, Dakhmphage and Jabbarphage (Arabic); Kyodaiphage (Japanese);
Biggiephage (Australian), Whopperphage (American); Judaphage (Chinese),
Enormephage (French); and Kaempephage (Danish).
Journal article: https://www.nature.com/articles/s41586-020-2007-4
Source: https://myfusimotors.com/2020/02/18/huge-bacteria-eating-viruses-close-gap-between-life-and-non-life/
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