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How certain gut microorganisms cause their neighbors to get infected with ‘zombie’ viruses

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Some gut bacteria have a strange superpower: they can reanimate viruses that have been dormant in other microorganisms.

The lab of Howard Hughes Medical Institute Investigator Emily Balskus originally released a preprint on bioRxiv on February 23, 2022, and then in the journal Nature on February 23, 2022. This viral awakening unleashes full-blown infections that kill virus-carrying cells. They discovered that a mysterious chemical called colibactin may awaken the killer viruses from their hibernation.

In the confined surroundings of the gut, microbes often produce toxic substances to assault one another. But, according to Balskus, a molecular scientist at Harvard University, colibactin stands out among these chemical weapons. “It doesn’t kill the target species directly, which is what we generally conceive of bacterial toxins doing inside microbial communities,” says the researcher. Instead, colibactin modifies microbial cells just enough to activate latent — and fatal — viruses hidden in the genomes of particular bacteria.

Humans have long sought after the powerful substances produced by microorganisms. Breck Duerkop, a bacterial virus researcher at the University of Colorado School of Medication, says, “We know a lot about their chemical characteristics, we purify them in the lab, and we utilize them as medicine, including antibiotics.”

But, according to Duerkop, who was not involved in this study, why bacteria generate these substances and what impact they have on nearby species remain unanswered concerns. Balskus’s latest piece, he says, is “a step in the right direction.”

Dark matter that is chemical

For years, scientists have known that colibactin may cause havoc in human cells. According to research conducted by Balskus and others, the substance destroys DNA, which may lead to colorectal cancer. Establishing a link between this chemical and sickness, on the other hand, was exceedingly difficult.

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A French study discovered in 2006 that mammalian cells exposed to the gut bacterium E. coli experienced catastrophic DNA damage. The damage was connected to a cluster of E. coli genes that encode machinery for constructing complex molecules, according to the researchers. The molecule, dubbed colibactin, proved very difficult to investigate. Researchers were unable to extract it from the E. coli that produced it despite several attempts.

Colibactin is one of numerous ephemeral chemicals that microorganisms are thought to produce. This “chemical dark matter,” like unseen dark matter particles in space, requires novel research methods. Balskus employs indirect ways to analyze these mysterious chemicals as part of her research on the gut’s microbial chemistry.

Her team has spent the last ten years investigating the microbial machinery that produces colibactin. Her team put together the structure of colibactin and discovered that it damages DNA by making erroneous connections inside the double helix.

Based on this research, other researchers discovered a solid relationship between the chemical and cancer: the molecule’s unique fingerprints present in genes that cause colorectal tumor development.

Viruses have a purpose

COVID-19 was the starting point for Balskus’ most recent colibactin investigation. Her group, like many others, had to restructure things in order to decrease physical contact between researchers. Postdoc Justin Silpe and graduate student Joel Wong found themselves working next to one other for the first time as a result of the reshuffle. During their discussions, they and Balskus were curious in how colibactin impacted other microorganisms in a crowded gut.

They discovered early on that introducing colibactin-producing bacteria to non-producers had minimal impact, suggesting that the chemical isn’t very lethal on its own. Silpe and Wong were unsure if colibactin, a big, unstable molecule, could even penetrate bacterial cells and cause DNA damage. They then pondered whether there was a third party involved, such as bacteria-infecting viruses. These viruses, which are nothing more than pieces of genetic information, may enter into bacteria’s DNA and wait patiently. Then, once activated, they generate an infection that detonates like a landmine within the cell.

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When the researchers cultured colibactin makers alongside bacteria that carried latent viruses, they saw an increase in viral particles and a decrease in the development of several virus-containing bacteria. This indicated that the chemical was responsible for an increase in active, cell-killing infections. The researchers discovered that colibactin enters bacteria and damages DNA. The virus rouses as a result of the damage, which rings a cellular wake-up bell.

Many microorganisms seemed to have built-in defenses against colibactin. In a broad range of bacteria, Balskus’ group discovered a resistance gene generating a protein that neutralizes the chemical.

Though colibactin is undoubtedly harmful, Balskus believes it may be used for more than simply killing. Both DNA damage and woken viruses, for example, might cause genetic alterations in surrounding bacteria rather than death, possibly boosting colibactin production.

The findings of Balskus’ team imply that cancer might be a side effect of whatever colibactin-producing bacteria are up to. “We’ve always thought that bacteria created this toxin in some manner to target other germs,” she explains. “From an evolutionary standpoint, acquiring it to target human cells didn’t make sense.”

Balskus will next look into how the molecule affects the gut microbiota, specifically which microorganisms vanish and which flourish following exposure to the compound. “Understanding the impact of colibactin on the microbial population and how its production is regulated might be the key to avoiding cancer,” she adds.

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