Plumbing the depths of women’s bladders may shower researchers with viral gold.

In a wee survey, Loyola University Chicago researchers found the sac-like organ brimming with never-before-seen viruses that can kill and manipulate bacteria. Their findings, published this week in the Journal of Bacteriology, offer a first-pass catalogue of the rich diversity of bacteria-infecting viruses—aka “phages” or “bacteriophages”—in the bladder microbiome. The researchers suggest that further studies into the streaming viral content could one day lead to phage-based methods to void bacterial infections and identify disorders.

“The thought that there’s not bacteria in urine is false,” Catherine Putonti told Ars straight away. Putonti, a bioinformatics researcher and microbiologist at Loyola, is the leading author of the study. “The big picture is that there are a lot of viruses that are part of these bacterial communities as well.”

With an early hold on what viruses are present in the bladder, the researchers are excited for more urinary deep dives to see if there’s a core “bladder phageome” and what those viruses might be doing—or be able to do. “Now we can start asking questions,” Putonti said.

Data drip

Phages have long been considered potentially valuable tools for manipulating and killing bacterial populations. The viruses exclusively infect bacteria, and individual phage species typically infect and kill a narrow range of types of bacteria. Doctors in some former Soviet republics, namely Georgia, use phage to treat infections, Putonti notes. But on the whole, researchers still don’t know enough about the viruses to use them safely and effectively, and any current treatments are considered experimental. In fact, researchers are still trying to get a handle on inventorying phage in various microbial communities—like that of the bladder.

Additionally, phages can cause different types of infections, typically either lytic or lysogenic. In lytic infections, the viruses invade bacterial cells, usurp their cellular machinery to make copies of itself, then bust the cell open (lyse) so that the viruses can go forth and storm more cells. These types of phage are considered potentially useful for therapies. For instance, if a phage species invades a particular pathogen—say, a toxic E. coli species—that’s causing an infection in a patient, unleashing legions of that phage could blast the pathogen’s population and help clear the infection.

In lysogenic infections, phages invade bacterial cells but then sneak their genetic code into that of the bacterium’s, sometimes disrupting genes. The bacteria then pass on their dormant, genetic stowaways to subsequent generations. In this stage, the quiet phage genes are called “prophages.” In the right conditions—say, if the bacteria are damaged, stressed, or exposed to certain conditions—prophages can awaken. When they do, they cut themselves free from the bacterial genome, start making viral clones, and burst from the cell. In other words, they switch to a lytic infection.

Lysogenic phages aren’t always bad for their bacterial hosts, though. They can also be incredibly helpful because they can move around genetic code. When they break themselves free of a bacteria’s genome, they may also swipe useful code. They can then tote that code into the genome of their next host. For instance, bacteria that cause cholera, botulism, and dysentery all do so with the help of toxins encoded by prophage.

Viral leak

For the new bladder phage study, Putonti and colleagues at Loyola focused on the more complex lysogenic phages in urine. They surveyed about 170 urine samples from women with or without urinary tract issues. The samples were collected by colleagues studying those issues in women. They collected the urine using catheters so that skin or vaginal bacteria didn’t sneak in.

From the tinkle, the researchers fished out 181 bacteria spanning the diversity of microbes in the bladder and sequenced their genomes. The researchers then analyzed those bacterial genomes using a pre-existing automated tool called VirSorter, which uses probabilistic modeling and viral genetic data to scan for known and likely prophage sequences.

The researchers found 457 potential phage sequences hiding in the bacterial genomes. About 86 percent of the bacterial genomes had one or more phage, and some had as many as 10 phage sequences. Of the 457 sequences, 226 were considered high-confidence sequences, and the remaining 231 were low confidence. A closer look found that most of the low-confidence hits were partial sequences or defunct prophage remnants. For the 226 high-confidence viruses, 97 were similar to prophages found before and 129 were never-before-seen virus sequences.

Though it’s early to understand health implications, the researchers noted that certain Actinomycetaceae phages were only found in women with overactive bladders. Such tidbits hint that phages are playing a role in health, the authors said.

Overall, just seeing things that have never been seen before is exciting, Putonti told Ars. But there’s also “a lot of exciting work that has to be done to look into the efficacy of phage as a replacement of antibiotics.”

Currently, Putonti and her team are going through the individual phage to see what they do and which bacteria they can kill. Ultimately, she said, we’ll ask “can we use these phage to shape microbial communities?”

Journal of Bacteriology, 2018. DOI: 10.1128/JB.00738-17 (About DOIs).