Bizarre pouvoir bactérien : comment certains microbes intestinaux réveillent des virus zombies chez leurs voisins.

Concept de Bactéries Dangereuses

Les bactéries intestinales fabriquent toutes sortes de produits chimiques, mais nous ne savons pas ce que font la plupart d’entre elles. Une nouvelle étude suggère que l’un de ces composés, précédemment lié au cancer, pourrait servir d’arme bizarre dans les escarmouches microbiennes.

Certaines bactéries intestinales ont un super pouvoir effrayant : elles peuvent ranimer des virus dormants qui se cachent dans d’autres microbes.

Ce réveil viral déclenche des infections à part entière qui détruisent les cellules porteuses du virus. Le laboratoire d’Emily Balskus, chercheuse à l’Institut médical Howard Hughes, a d’abord publié une préimpression sur bioRxiv.org, puis dans la revue Nature le 23 février 2022. Une molécule cryptique appelée colibactine peut faire sortir les virus tueurs de leur sommeil, ont-ils découvert.

Les microbes génèrent souvent des composés nocifs pour s’attaquer mutuellement dans les quartiers exigus de l’intestin. Mais parmi ces armes chimiques, la colibactine semble inhabituelle, explique Balskus, biologiste chimiste à l’université de Harvard. “Elle ne tue pas directement les organismes cibles, ce qui est normalement le cas des toxines bactériennes au sein des communautés microbiennes.” Au lieu de cela, la colibactine modifie les cellules microbiennes en activant des virus latents – et mortels – cachés dans le génome de certaines bactéries.

Virus zombie de la bactérie intestinale

Certaines bactéries intestinales produisent une molécule, appelée colibactine, qui réveille les virus infectieux (rouge foncé) tapis dans les génomes des microbes voisins. Crédit : Illustration Fairman Studios, LLC

Les humains recherchent depuis longtemps les composés puissants que les microbes produisent. “Nous en savons beaucoup sur leurs propriétés chimiques, nous les purifions en laboratoire et nous les utilisons comme médicaments, notamment comme antibiotiques”, explique Breck Duerkop, qui étudie les virus bactériens à la faculté de médecine de l’Université du Colorado.

Mais la raison pour laquelle les bactéries fabriquent ces composés et les effets qu’ils ont sur les organismes voisins sont des questions ouvertes, déclare Duerkop, qui n’a pas participé à cette recherche. Il considère que les nouveaux travaux de l’équipe de Balskus sont “un pas dans la bonne direction”.

Matière noire chimique

Les scientifiques savent depuis des années que la colibactine peut faire des ravages sur les cellules humaines. Les recherches menées par Balskus et bien d’autres ont montré que ce composé endommage 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. coli genes 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 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.

“We always suspected that bacteria made this toxin to target other bacteria in some way.”

Emily Balskus, HHMI Investigator at Harvard University

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 actually 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.

Reference: “The bacterial toxin colibactin triggers prophage induction” by Justin E. Silpe, Joel W. H. Wong, Siân V. Owen, Michael Baym and Emily P. Balskus, 23 February 2022, Nature.
DOI: 10.1038/s41586-022-04444-3
bioRxiv

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