Can viruses be used to treat diseases? Phage therapy - defeating magic with magic!

Author: Zhao Bei

In our impression, viruses are often the source of infection that causes diseases or even cancer. They are easy to mutate and have limited treatment methods, which makes people shudder. However, there is a type of virus that has been regarded by scientists as a promising drug for treating bacterial infections since its discovery. That is bacteriophages. Scientists' research and transformation of bacteriophages even predates the currently commonly used antibiotics. Although research progress is slow, phage therapy is gradually showing advantages that antibiotics do not have, and can play a role in diseases such as enteritis, sepsis, and infections in different parts of the body.

Bacteriophages, as the name implies, are viruses that use bacteria as hosts. Bacteria can infect plants and animals, while bacteriophages can infect bacteria and replicate in them. Sometimes they can directly cause bacterial lysis, and the released bacteriophages will then look for the next host. Where there are bacteria, there are bacteriophages, and our bodies are no exception. There are billions of bacteriophages parasitizing in the bacterial flora in our skin, intestines and other parts.

Figure 1. Bacteriophages preying on bacteria

A major feature of phage infection of bacteria is selectivity . One phage can only use one type of bacteria. If the phage's tail fiber protein happens to adapt to the protein or lipopolysaccharide on the bacterial surface, it is like a key inserted into a keyhole, and the bacterial door will open to the phage.

It is precisely because of this characteristic of phage infection of bacteria that it has an advantage that antibiotics do not have, that is, it is targeted when killing bacteria. Currently commonly used antibiotics, such as penicillin, cephalosporin, tetracycline, azithromycin, vancomycin, etc., will kill a large number of bacteria when taken. Each time we are infected by pathogens, there may be only one or two, such as Staphylococcus aureus, Clostridium difficile, etc., but the indiscriminate attack of antibiotics will also eliminate our own intestinal flora, truly killing one thousand enemies and injuring eight hundred of our own.

Another thorny problem is the increasing number of drug-resistant pathogens. Antibiotics are completely ineffective against them because they are the survivors who have escaped antibiotics. After being screened by antibiotics, the non-resistant ones have died, while the resistant ones have gradually grown stronger. Some pathogens can even escape the attack of multiple antibiotics, and we are helpless against these multi-drug resistant super pathogens and can only rely on our own immune system to resist.

In addition to research and development experiments in the laboratory, phage therapy also has a few clinical cases. One of the patients was a 68-year-old American who had a multidrug-resistant Acinetobacter baumannii infection near his pancreas. When the combination of multiple antibiotics was ineffective, the patient fell into a coma and kidney failure, facing the threat of death. The University of California, San Diego, which treated him, applied for the use of phage therapy and obtained FDA approval. In the end, the patient received a treatment containing 9 phages, which controlled the bacterial infection and gradually improved various physiological indicators. The phage treatment lasted a total of 11 weeks. After 245 days of observation in the hospital, the patient recovered and returned home to return to work.

Another recently published study showed that a cocktail therapy consisting of a mixture of five bacteriophages can inhibit the reproduction of multidrug-resistant Klebsiella pneumoniae in patients with enteritis, thereby treating enteritis caused by it. The study has now entered Phase I clinical trials [1].

Since phage therapy can save lives, why has it not been used on a large scale in clinical practice?

The research on phage therapy has always faced many difficulties. Since the first case of phage curing dysentery in 1919, it has been developing slowly and continuously with stops and starts.

Standardization of phage therapy is difficult. First of all, phage therapy is often not a single phage, but a mixture of several phages. Different combinations must be designed for different infections. Each disease needs to be customized and optimized. If the wrong phage strain is selected in the combination, it will not have a bactericidal effect. If too many are selected, it will be a waste, the cost is high, and standardization is even more difficult.

Phage therapy also has the problem of drug resistance. Since there are multi-drug resistant bacteria, there will also be phage-resistant bacteria. In some cases of treating patients, scientists have detected bacteria that can escape phage invasion. They either change the structure of the receptors on their cell surfaces that bind to phages, or destroy the phage genome after the phage invades their own cells to achieve self-defense.

Although the bacteria want to escape, the phage will not sit still and wait for death. After all, it cannot survive without its host. Since the structure of the receptor protein on the surface of the bacteria will change, the fibers on the tail of the phage, which is the part used to bind to the bacteria, will also change. This kind of co-evolution of chasing each other is vividly reflected in the relationship between pathogenic Escherichia coli and the phages that attach to it[2]. Some phages also carry methyltransferases that can protect their own genomes from being destroyed by host bacteria[3], allowing them to successfully replicate and reproduce in the host body.

These characteristics of phages and their ability to evolve rapidly have always made scientists full of hope for phage therapy. By utilizing their own characteristics and combining them with gene editing technology, more stable phage therapeutic drugs may be developed. In addition, there is also a broad space for the development of other flora-related diseases (such as tumors, metabolic diseases, etc.) by targeted elimination of "bad bacteria" and retention of "good bacteria". Although the road ahead is still full of difficulties, in the face of the threat of super-resistant bacteria, humans may really need to turn to phages, the smallest organisms, and invest more time and cost in the research and development of phage therapy.

1. FedericiS, Kredo-Russo S, Valdés-Mas R, et al. Targeted suppression of humanIBD-associated gut microbiota commensals by phage consortia for treatment ofintestinal inflammation. Cell. 2022;185(16):2879-2898.e24.

2. Salazar, KC; Ma, L.; Green, SI; Zulk, JJ; Trautner, BW; Ramig, RF; Clark, JR; Terwilliger, AL; Maresso, AW;

3. Murphy, J.; Mahony, J.; Ainsworth, S.; Nauta, A.; van Sinderen, D. Bacteriophage orphanDNA methyltransferases: Insights from their bacterial origin, function, and occurrence. Appl. Environ. Microbiol. 2013, 79, 7547–7555.