Phages: friends or foes? A newly discovered mechanism where bacteria use bacteriophages to work against our immune system

By Jackson Campbell

            March 8^th, 2019 marked the ninety year and six-month anniversary of Alexander Fleming’s accidental discovery of penicillin, the first antibiotic to be used for medical purposes. What followed this discovery was a revolution in medicine and science as we discovered new antibiotic mechanisms to employ and rapidly became proficient in producing antibiotics en masse. Fleming’s discovery has undoubtedly saved countless lives from a variety of otherwise resilient and deadly bacterial pathogens. But alas, today we find ourselves facing a crisis point as the medical foundation we’ve built upon antibiotics is in jeopardy. Overuse of antibiotics in disease treatment and agriculture has created a bottleneck of selective pressure on bacteria, forcing them to evolve and adapt much faster than normal to survive. Consequently, antibiotic resistant bacteria were discovered as early as 1940. These resistant strains have continued to grow and evolve rapidly ever since: twenty-two years later we discovered one of the most infamous bacterial pathogens with the original Methicillin Resistant Staphylococcus aureus (MRSA) strain. Today, most bacterial infections that are picked up from hospital care are from bacterial “superbugs” that are highly pathogenic and practically immune to all but a small number of “last-resort” antibiotics such as Vancomycin and Linezolid. As such, it has become paramount that we discover new methods for antibacterial treatment before our last bastion of defense is neutralized.

            One such alternative method that has been investigated over the last two decades is phage therapy. Phage therapy involves the use of bacteriophages, viruses that infect and propagate using bacteria as their host, to attack invading pathogenic bacteria. In terms of combating antibiotic resistant bacteria, phage therapy is particularly promising for two reasons. Firstly, the bacteria’s antibiotic resistance mechanisms do not prevent against bacteriophage infection, which allows us to circumvent their defenses. Secondly, while bacteria can evolve or utilize certain defense mechanisms against phage infection, such as the CRISPR-Cas adaptive immune system, bacteria are limited in the number of defense mechanisms they can activate simultaneously. Because of this, combination treatment with antibiotics AND phage therapy has potential to be an effective tactic to combat these superbugs.

            With some successful clinical trials for a variety of bacterial infections being reported all across the world, the use of phage therapy as an alternative antibacterial treatment method seems within our grasp. However, it would behoove us to fully understand the benefits, limits, and consequences of using phage therapy before employing it on a major scale. One recent study that serves something of a cautionary tale is the discovery of Pseudomonas aeruginosa (Pa) utilizing bacteriophages to help infect hosts in a mouse model. Pa commonly carry a strain of bacteriophage known as Pf4. This phage is a lysogenic phage, meaning it doesn’t replicate rapidly on its own but instead integrates its genome into the bacterial host’s circular chromosome and replicates alongside its daughter cells through natural division. Furthermore, it is a non-lytic phage; when its offspring eventually leave the bacterial host, they do so without killing it.

            The study in question initially reveals that Pa bacteria that carry the Pf4 phage are more efficient at infecting surface wounds than those without the phage. Specifically, they found that in a mouse model they were able to colonize more wounds faster (measured as “infection rate”) and had increased mortality and morbidity (measured by percent survival and weight loss of survivors, respectively). Upon further investigation into the mechanism behind this, they found that the Pf4 phages could be recognized by macrophages and trigger an antiviral immune response. This benefits the invading bacteria because, similar to the aforementioned phage vs. antibiotic defense limitations for bacteria, mammalian immune systems are also limited in the number of defense mechanisms they can simultaneously activate. In fact, most of the mechanisms behind antiviral immune response in humans reduce or completely counteract our antibacterial immune response. Therefore, the antiviral response from the Pf4 phage suppresses any antibacterial activity and allows the Pa bacteria to slip by the immune system unimpeded.

            The results of this study show us that bacteriophages may not be the foolproof solution to our antibiotic resistant bacteria crisis. However, while this study may appear to rattle the foundation of phage therapy at first glance, there is still hope for its continued use and development. As previously stated, the Pf4 phage in this study is a lysogenic, non-lytic phage that can grow inside the bacteria without harming it. Conversely, the bacteriophages studied and used in phage therapy are limited to broad-spectrum, lytic phages (i.e., only phages that can infect and kill a wide variety of bacterial targets). Thus far, there has been no evidence to suggest that lytic phages can induce an antiviral immune response the same way these lysogenic phages do. Nonetheless, this study should keep us cautious that this could be an undiscovered possibility for lytic phages. Ultimately, this study benefits the continued development of phage therapy by revealing a potential adverse effect we can screen for when identifying, isolating, and manufacturing new strains of phage for future research.

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Jackson Campbell is a 4^th year PhD student in the Driskill Graduate Program at Northwestern University. He is currently pursuing his PhD in Microbiology/Immunology and is investigating the unique role the CRISPR-Cas system plays in Legionella pneumophila infection. Jackson previously graduated from University of the Pacific with a B.S. in Biological Sciences and has worked as an intern for the RISE and SROP programs at Stanford and Northwestern, respectively. Outside of lab his hobbies include guitar, creative writing, and gaming (especially Pokémon and Super Smash Bros.)  He’s seldom seen without his favorite pair of headphones.

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