The ransom of viruses: how to use them to protect ourselves from superbugs

The ransom of viruses

Viruses don't look anyone in the face when it comes to replicating. And if sometimes it is our body that pays the price, in some cases even our pathogens can end up on the menu: in the right conditions, therefore, viruses can then turn into powerful antibacterial agents. We are talking about phages, or bacteriophages, viruses specialized in parasitizing bacteria, and destroying them to propagate their own genetic material. Their therapeutic use is called phage therapy. It has a century-long history, had fallen into disuse in the West in the post-war period, and is recently being rediscovered to address one of the most terrible emergencies that await us in the coming decades: the advance of resistant bacteria, and the decline in the effectiveness of antibiotics that threaten to make lethal infections once again usually trivial and easily treatable.

Incurable patients Recently, the case of a Belgian woman, suffering from a multidrug-resistant infection, has recently drawn attention to phage therapy. survived the attacks of 22 March 2016 in Brussels. Struck by an explosion at the city airport, the woman had survived the heavy injuries but in the hospital she had contracted Klebsiella Pneumonie in a form resistant to almost every known antibiotic. After almost two years of waiting, in 2018 the doctors of the Queen Astrid Military Hospital managed to treat the patient with a cocktail of phages and antibiotics, which finally cured the infection, and allowed the woman to walk again.

The reasons for such a long wait are simple: in Europe there is no regulatory framework for the use of phages, and in many countries it is possible to resort to these therapies only in the context of clinical studies and experimental settings . After the success of 2018, Belgium was one of the first EU countries to adopt legislation dedicated to bacteria-killing viruses, and has since become one of the most active European centers where phages are used for the treatment of resistant infections. "Phage therapy is becoming more common, at least in Belgium - said a few months ago on the pages of the New Scientist Jean-Paul Pirnay, of the Queen Astrid Military Hospital in Brussels - it has now coordinated phage treatments in over a hundred patients ".

The term coordinate is not accidental: it is not the doctors of the Belgian hospital that produce the preparations with which the patients are infused, but one of the main centers of research and clinical use in this field , located well outside the borders of the Union: the Eliava Institute in Tblisi, Georgia. Practically the temple of phage therapy, where these viruses have been studied and used for the treatment of a multitude of bacterial diseases for almost 100 years. In the Soviet world, in fact, phages have always been used, alongside or in place of the antibiotics used in the West. Here, however, they have been almost forgotten in the last 70 years, and only recently are they returning to attract the interest of researchers and pharmaceutical companies. Explaining why requires a mention of the history of these therapies, and the nature of these peculiar microorganisms.

A history of science and politics Phages are among the types of viruses most studied by the scientific community, and also one of the more common in nature: some estimates say that there are more bacteriophage viruses (or phages) on the planet than the sum of any other organism, including bacteria. There are many types of them, but in principle they all act in a similar way: they recognize a specific bacterium (sometimes even a specific strain of bacteria) thanks to a receptor present on its membrane, they anchor themselves there, and inject their material genetic (dna or rna that is) inside. When this happens, the genetic material of the virus exploits the bacterium's structures to make new copies of itself, and eventually the bacterium dies from lysis of its membrane, releasing new copies of the virus into the environment.

Their discovery dates back to the early 1900s, and is contested by two microbiologists, the Englishman Frederick Twort and the French-Canadian Felix d'Hérelle. Their nature was initially unclear. Some thought that they were bacteria in an early stage of their life cycle, others that they were enzymes produced by the human body or by the bacteria themselves, others (correctly, as it was later established) considered them viruses. They were known to somehow kill bacteria such as those that cause cholera and dysentery. And therefore the discovery immediately aroused strong interest in the medical field: antibiotics had not yet been invented, and a microorganism that kills bacteria could prove to be precious as a cure for the many infectious diseases for which there was no therapy.

Formulations were developed to treat various diseases, and forms of prophylactic therapy, used for example by the Soviet army during World War II, to prevent infections. Demonstrating the effectiveness of these preparations was not easy: the technological limitations of the time made the production quality of the solutions used by doctors fluctuating; Randomized clinical trials had not yet been invented, and scientific consensus in medicine was based more on distinguished opinions and individual observations than on incontrovertible scientific data. Some doctors considered them valuable, particularly in the Soviet Union, others a colossal hoax, at least in their clinical use. With the arrival of antibiotics in the 1950s, they rapidly declined in the West. It was not the same in the countries of the Soviet bloc, where phage therapy continued to be studied, with mixed success, throughout the 1900s. In particular in Tbilisi, where one of the most advanced institutes in the world dedicated to phage therapies is still located.

Pros and cons To rekindle the interest of Western science in phages, as we said, is was the current antibiotic efficacy crisis. In 2019 alone, deaths from resistant superbugs may have exceeded one million. And it is estimated that, in the worst-case scenario in which no new molecules or antibacterial strategies are found in the next few decades, annual superbug deaths could exceed 10 million by 2050.

In such a situation, phages have many palatable characteristics. Their mechanism of action is completely different from that of antibiotics, and therefore a bacterium that develops drug resistance is still susceptible to the action of bacteriophage viruses. Furthermore, their range of action is much more limited than that of antibiotics. This characteristic initially proved to be a limitation: broad-spectrum antibiotics can be prescribed without having to ascertain the nature of the infection, while the use of phages is only possible when the pathogen to be combated is known, and therefore requires execution. of relatively complex analyzes, which are currently not routinely carried out in the face of the first sign of infection.

Precisely because of their specificity of action, however, phage therapies have almost no side effects, they do not affect the flora intestinal or other microbiomes in the body, and do not help to further select strains of bacteria resistant to antibiotics. As a therapy they also have a low cost, and according to some researches (to be confirmed, given that their clinical use is still quite limited) they seem even more effective than antibiotics in eliminating bacterial infections.

Limits and developments future In addition to the aforementioned need to identify the pathogen responsible for an infection, before being able to choose the right virus to kill it, phage therapy also has other important limitations. Being viruses, their action can facilitate the transfer of genetic material between different bacteria. And this, at least in theory, could induce the emergence of new bacterial strains, made more virulent or antibiotic - resistant by the insertion of genes from the pathogens that it was desired to fight with phages.

Again due to their viral nature, phages are subject to the action of the immune system, which can reduce their therapeutic efficacy, especially in the case of repeated or prolonged administration. Lastly, as in the case of antibiotics, bacteria can also become resistant to phages over time. This is why these viruses are unlikely to be able to replace antibiotics in the fight against bacterial infections. Instead, it is more likely to imagine a coaching, as a last line of therapy in case of resistant infections (as is now the case, mostly at an experimental level), as a combined therapy to improve the action of antibiotics, or as an alternative therapy that expands therapeutic opportunities , and reduces the pressure towards the development of antibiotic resistance.

At the Eliava Institute in Tbilisi they are already a consolidated reality. The Georgian researchers - Lia Nadareishvili, a specialist of the institute, tells AFP - have six phage cocktails that cover a broad spectrum, active against various bacterial diseases. When the preparations do not prove effective, which happens in about 10-15% of patients, we proceed to search for a virus that works among those present in the database of the institute, or by hunting for new species in the wastewater, or in areas contaminated by the presence of the bacterium that is to be destroyed.

Outside Georgia, for several years now there have been many small companies in the world of biotechnology that are developing phage therapies. Among those in the most advanced stages are therapies against periprosthetic infections and urinary tract infections, and against Pseudomonas aeruginosa infections in patients with cystic fibrosis. To see phage therapies really take off, however, a radical change will be needed at the legislative level: simplifying research and the clinical use of these preparations will also increase Big Pharma's interest in small phages, and at that point it is likely that the results they will begin to accumulate quickly.