How some gut microbes awaken 'zombie' viruses in their neighbors

Date:
February 23, 2022
Source:
Howard Hughes Medical Institute
Summary:
Gut bacteria brew all sorts of chemicals, but we don't know what
most of them do. A new study suggests that one such compound,
previously linked to cancer, may serve as a bizarre weapon in
microbial skirmishes.



FULL STORY ==========================================================================
Some gut bacteria have a spooky superpower: they can reanimate dormant
viruses lurking within other microbes.


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This viral awakening unleashes full-blown infections that destroy the
virus- carrying cells, Howard Hughes Medical Institute Investigator Emily Balskus's lab first published as a preprint on bioRxiv and later in the
journal Natureon February 23, 2022. A cryptic molecule called colibactin
can summon the killer viruses from their slumber, they found.

Microbes often generate noxious compounds to attack one another within
the cramped quarters of the gut. But among these chemical weapons,
colibactin appears unusual, says Balskus, a chemical biologist at
Harvard University. "It doesn't directly kill the target organisms,
which is what we normally think of bacterial toxins doing within
microbial communities." Instead, colibactin tweaks microbial cells
just so, activating latent -- and lethal -- viruses tucked away in some bacteria's genomes.

Humans have long sought out the potent compounds that microbes
produce. "We know a lot about their chemical properties, we purify
them in the lab, and we use them as medicine, including antibiotics,"
says Breck Duerkop, who studies bacterial viruses at the University of
Colorado School of Medicine.

But why bacteria make these compounds and what effects they have on
neighboring organisms are open-ended questions, says Duerkop, who was
not involved in this research. He calls Balskus's teams new work "one
step in the right direction." Chemical dark matter Scientists have
known for years that colibactin can wreak havoc on human cells.

Research by Balskus and many others has shown that the compound damages
DNA, which can lead to colorectal cancer. But establishing a connection
between this compound and disease proved particularly formidable.



==========================================================================
In 2006, a French team reported that mammalian cells that encountered the
gut bacteria E. coli suffered fatal damage to their DNA. The researchers
linked this damage to a cluster of E. coligenes encoding machinery
for building a complex molecule. Dubbed colibactin, the molecule was extraordinarily difficult to study. After many tries, researchers simply couldn't isolate it from the E.

coli making it.

Colibactin is one of many ephemeral compounds that scientists suspect
microbes make. Like invisible particles of dark matter in space, this
"chemical dark matter" requires creative means to study. As part of
her exploration of the gut's microbial chemistry, Balskus uses indirect approaches to examine these elusive molecules.

Over the past 10 years, her team has probed colibactin by studying the microbial machinery that manufactures it. She and her colleagues have
pieced together colibactin's structure and determined that it damages
DNA by forming errant connections within the double helix.

Building off this work, scientists elsewhere uncovered a definitive link
to cancer: the molecule's distinctive fingerprints appear in genes known
to drive colorectal tumor growth.

A role for viruses Balskus's most recent colibactin study got its
start with another disease: COVID-19. Like many other labs, hers had to rearrange things to reduce physical contact among researchers. As part
of the reshuffling, postdoc Justin Silpe and graduate student Joel Wong
ended up working near one another for the first time. Their conversations
led them and Balskus to wonder how colibactin affected other microbes
in a crowded gut.



========================================================================== Early on, they found that exposing colibactin-producing bacteria to non- producers had little effect, suggesting that, on its own, the molecule
isn't particularly deadly. Silpe and Wong weren't sure if colibactin, a
large, unstable molecule, could even enter bacterial cells to damage their
DNA. They then wondered if a third party -- bacteria-infecting viruses --
might be involved. Hardly more than bits of genetic information, these
viruses can slip into bacteria's DNA and lie quietly in wait. Then, once triggered, they cause an infection that blows up the cell like a landmine.

When the researchers grew colibactin producers alongside bacteria carrying
such latent viruses, they saw the number of viral particles spike, and
the growth of many virus-containing bacteria drop. That suggested the
molecule sparked a surge in active, cell-killing infections. Colibactin
does indeed enter bacteria and damage DNA, the team showed. That damage
sounds a cellular wake-up bell that rouses the viruses.

Many microbes appeared equipped to protect themselves against colibactin.

Balskus's lab identified a resistance gene encoding a protein that
neutralizes the compound in a wide variety of bacteria.

Though colibactin clearly has a dangerous side, it may serve as more
than just a lethal weapon, Balskus says. For example, both DNA damage
and awakened viruses can also induce genetic changes, rather than death,
in neighboring bacteria, potentially benefiting colibactin producers.

Balskus's team's discoveries suggest that cancer may be collateral damage caused by whatever else colibactin-producing bacteria are doing. "We
always suspected that bacteria made this toxin to target other bacteria
in some way," she says. "It didn't make sense from an evolutionary
perspective that they acquired it to target human cells." Next, Balskus
plans to investigate how the compound alters the community of microbes
in the gut -- which ones disappear and which thrive after exposure to
the compound. "The key to preventing cancer may be understanding the
effects colibactin has on the microbe community and how its production
is controlled," she says.

========================================================================== Story Source: Materials provided by Howard_Hughes_Medical_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Silpe, J.E., Wong, J.W.H., Owen, S.V. et al. The bacterial toxin
colibactin triggers prophage induction. Nature, 2022 DOI:
10.1038/s41586- 022-04444-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220223111242.htm

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