Virus versus bacteria: Study discovers phage to fight dysentery

• Bacillary dysentery resulting from Shigella bacteria kills about 160,000 people globally every year.
• Treating this disease remains a challenge, as antibiotic resistance is rising across the globe.
• In their search for an alternative treatment, Yale University researchers in New Haven, CT, discovered a naturally occurring bacteriophage, or phage, that can neutralize or weaken Shigella bacteria.
• This study demonstrates the potential benefits of using viruses against bacteria for public health.

Yale University scientists have unexpectedly found a potential weapon against a family of bacteria called Shigella in phages, which are viruses that can infect and break down bacteria from within.

By pitting these natural enemies against each other, the researchers saw that a bacteriophage called A1-1 was effective against the resistant and mutant Shigella bacteria.

Shigella bacteria cause shigellosis, a contagious infection marked by inflammatory diarrhea and dysentery.

Rising cases, antimicrobial resistance, and limited treatment options make this microbe a priority pathogen for the World Health Organization (WHO).

Shigellosis is responsible for about 125 million moderate-to-severe diarrhea cases annually. Most cases occur in children living in developing nations, where limited clean water, poor hygiene, and malnutrition contribute to transmission.

The study’s findings appear in the journal Applied and Environmental Microbiology.

Back to a time before antibiotics

The practice of phage therapy to fight human bacterial infections precedes penicillin use. In the mid-20th century, antibiotic use led to its abandonment.

Now, bacteria’s increasing resistance to antibiotics is “one of the biggest threats to global health, food security, and development,” says the WHO.

This was one of the reasons why Kaitlyn Kortright, Ph.D., Rachel E. Done, and Benjamin Chan, Ph.D. — scientists at Yale’s Department of Ecology and Evolutionary Biology and co-authors of the study — decided to work on an alternative solution to fight this resistance.

“Unfortunately, dysentery is widespread, and an approved vaccine for bacillary dysentery is not available. Until one is widely available, a phage-based approach to prevention via water treatment could greatly reduce the incidence of disease,” they told Medical News Today.

The researchers surprisingly discovered a naturally occurring phage that can reduce the spread of Shigella flexneri in the body. This strain causes the majority of dysentery cases in southern Asia and sub-Saharan Africa.

Before the study, scientists did not know that such a phage existed.

Evolutionary trade-offs in viruses

The study explores evolutionary trade-offs, an integral concept in evolutionary biology.

Evolutionary trade-offs happen when an organism develops characteristics that strengthen it in one way while weakening it in another.

Dr. Kortright explained:

“We sought to discover a phage that was naturally capable of binding to outer membrane proteins of S. flexneri responsible for virulent cell-to-cell spread of this pathogen in the human intestine, hypothesizing that evolution of phage resistance should alter, or eliminate, this virulence factor protein.”

The researchers hoped that their findings would lead to the designing of phage treatments that leveraged evolving phage resistance “as a possible clinical benefit.”

A ‘successful’ long shot

Dr. Kortright and her team focused on S. flexneri because of its resistance to conventional antibiotics. Moreover, the microbe is mainly active in low income regions, where antibiotics are either expensive or scarce.

Safe drinking water is an issue in these areas, as well. Dr. Kortright was hoping to find phages that “might even be useful for treating water sources, by selecting for avirulent S. flexneri.”

In a move they described as “clearly a long shot,” the researchers chose to look in Cuatro Cienegas, Mexico — an area known for prolific microbial biodiversity.

There, they discovered phage A1-1 in a wastewater sample. The authors hypothesized that this virus would destroy its host bacteria and select for the evolution of resistance in bacteria.

The team isolated five phage-resistant mutants. Upon exposure to A1-1, all the mutants “were incapable of intercellular spread.”

Pros and cons of phage therapy

Dr. Kortright and Dr. Chan weighed in on phage therapy’s potential:

“Phages targeting S. flexneri virulence, when used as part of a bioremediation or water sanitation project, could be very effective in reducing the severity/duration of a shigellosis outbreak or preventing an outbreak altogether.”

However, the co-authors noted that the number of phage particles necessary to treat active shigellosis could be financially unfeasible.

Also, direct administration might kill S. flexneri in the gut lumen, but it may not work as well when it comes to eliminating intracellular bacteria.

The co-authors feel that “additional measures would need to be considered before attempting to use phages therapeutically to treat intracellular bacteria.”

Nabeeh Hasan, Ph.D., a biomedical researcher at National Jewish Health with experience in phage therapy, told MNT that phage therapy was “an underutilized tool in our fight against harmful bacteria.”

“One benefit of using an appropriate phage is that they target specific bacteria and don’t infect animals, specifically humans. This results in no toxicity and minimal disruption to the natural flora. We can screen and select the appropriate phage for a specific harmful bacterium. This permits less induction of resistance. Phages can be applied in many formulations and penetrate bacterial biofilms, which are notoriously challenging to clear.”

– Prof. Nabeeh Hasan

Unfamiliar but promising weapon against bacteria

Like the study’s authors, Dr. Hasan sees phages as an imperfect solution:

“Each phage may be a one-trick pony and specifically target one bacterium or a very narrow range of bacteria. Phages are also live biological agents that can evolve while being manufactured, but this is no different than live-attenuated vaccines. The biggest drawback is that we aren’t as familiar with phages and phage therapy as we should be, so it sounds scary and unfamiliar.”

Dr. Hasan noted that dysentery is a leading cause of preventable death globally.

“Like many infectious diseases, dysentery is preventable by access to hygiene and clean water. We should fund more research to explore the possibility of phages as a means to increase clean water and as a viable alternative to antibiotics when appropriate,” he added.

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