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Phage Therapies for Multidrug-Resistant Infections Should Consider Host Response

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Multidrug-resistant (MDR) infections are a significant public health risk. One study estimates that bacterial antimicrobial resistance was responsible for 1.27 million global deaths in 2019.

Phage therapy (also known as bacteriophage therapy), which relies on the use of viruses that kill bacteria, has found success as an antimicrobial in Eastern Europe and is now seeing increasing use in clinical trials and compassionate use cases worldwide. Despite the success of phage therapy in treating MDR infections, there is still little data on the effects of phages on a human host.

What is phage therapy?

In phage therapy, bacteriophages bind to a unique bacterial receptor and inject their genetic material, which encodes all necessary components for creating progeny viruses. These components assemble and create new viruses, which are released by lysing the bacterial cell. Once all the bacteria are lysed, they’ll stop multiplying. Like other viruses, phages can lay dormant until more bacteria show up.

A study by scientists at the Geisel School of Medicine at Dartmouth, has shown that therapeutic phages can be detected by epithelial cells of the human respiratory tract, eliciting proinflammatory responses that depend on specific phage properties and the airway microenvironment.

These findings, published in PLOS Biology, suggest that interactions with a human host should become an important factor when considering the rational design of phage therapies. Additionally, the researchers suggest that it may be possible to harness immune responses to phages to improve phage therapy efficacy on a case-by-case basis.

Phages elicit unique immune responses

In the study, the researchers aimed to better understand how lytic phages interact with airway epithelium cells (AECs), a tissue site that is colonized by bacterial biofilms in several chronic respiratory disorders.

What are bacterial biofilms?

Bacteria biofilms are clusters of bacteria attached to a surface and/or to each other and embedded in a self-produced matrix. The matrix of the biofilm consists of substances such as proteins, polysaccharide and eDNA and offers additional protection to the bacteria. Within the biofilm bacteria can employ several survival strategies to evade the host's immune system.

Using a panel of Pseudomonas aeruginosa (P. aeruginosa) phages and human AECs from an individual with cystic fibrosis, the researchers determined that interactions between phages and AECs depend on specific phage properties as well as features of the microenvironment.

The airway epithelium also responds to phage exposure by altering its transcriptional profile and secreting phage-specific antiviral and proinflammatory cytokines.

“We found that diverse phages have different capacities to aggregate and persist in the airway environment, which could impact their ability to bind and infect their specific bacterial host,” Dr. Paula Zamora, postdoctoral associate at the Geisel School of Medicine at Dartmouth and lead author of the study, told Technology Networks.

“We also discovered that phages elicit different immune responses. In our case, some phages were more proinflammatory, while others triggered an antiviral immune response. Depending on the specific conditions of the microenvironment where the targeted microbes are residing, these immune responses could be exploited to improve the therapeutic effect of phages,” she added.

Potential benefits of phage therapy for treating MDR infections

The use of phage therapy has been limited due to the requirement of finding a phage that kills a particular bacterial strain. “Many academic and medical institutions are generating large phage libraries that will facilitate the process of selecting phages [to overcome this],” said Dr. Jennifer Bomberger, professor of microbiology and immunology at the Geisel School of Medicine at Dartmouth.

Phages lack some of the issues that regular antimicrobials have regarding broad-spectrum bacterial killing due to their specificity. Coupled with their ability to self-amplify, repeated treatments of phage therapies are thought to not be as necessary as regular antibiotics. However, more research is required to determine effective dosing for phage therapies.

“Many naturally occurring properties of phages can be exploited to improve their therapeutic efficacy. For example, some phages encode depolymerases and lysins that can degrade biofilm matrixes, which could help with phage penetration and binding to their bacterial host,” explains Bomberger.

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Understanding the effects of phages on the human body

Because phage replication is dependent on a bacterial receptor, there has been a long-standing belief that phages should be innocuous to mammalian cells.

“Even though phages cannot replicate in mammalian cells, phages can display pathogen-associated molecular patterns that can be recognized by immune pattern recognition receptors on human cells. Phages are released from bacterial cells by lysing them, which is key to their antimicrobial activity. This mechanism implies that bacterial components will also be released to the extracellular environment, which could amplify immune responses,” said Bomberger.

“Our study, as well as the few others that have evaluated phage therapy effects in the human host, agree that the immune responses appear to be self-limiting and without causing debilitating effects in the people that have received this therapeutic.”

Despite increasing clinical interest, there remains limited data on the effect of phages on a human host. Bomberger pointed out the time and money costs associated with the preparations of phages devoid of endotoxins and a lack of in vitro models as reasons behind the lack of data: “In this regard, we have had the advantage of several years of experience working with cell culture models that replicate the mucosal surface of the airways that positioned us well to carry out this research.”

Implications on personalized treatments for MDR infections

The FDA currently recommends phage, endotoxin content, sterility and lytic activity against the patient's bacterial strains be provided as part of the rational design of phage therapy. However, the effects of phages on human cells are not required to be evaluated as part of phage therapy design. “We hope that our findings might add interactions with the human host as one of the factors to be considered,” said Zamora.

Based on their findings the researchers propose that immune responses to phages could be harnessed to improve phage therapy efficacy on a case-by-case basis. Evaluating immune responses could also help with phage selection when faced with phages of similar bacterial specificity. Some phages have also been shown to elicit the generation of neutralizing antibodies, which could reduce phage therapy efficacy.

Zamora concludes: “We hope that our findings will lead to more studies examining the effect of phages in the human host. To be able to do that, we need to develop better assays that recapitulate phage activity, maybe by including different cell types, polymicrobial biofilms, mucus, and other factors that mimic the mucosal environment in the airways of people with chronic lung disease.”

Dr. Paula Zamora and Dr. Jennifer Bomberger were speaking to Blake Forman, Senior Science Writer & Editor for Technology Networks.

About the interviewees:

Dr. Paula Zamora is a postdoctoral associate at the Geisel School of Medicine at Dartmouth. She received her PhD from Vanderbilt University. Her current research focuses on cellular responses to therapeutic phages and other insults in the lungs of individuals with cystic fibrosis.

Dr. Jennifer Bomberger is a professor of microbiology and immunology at the Geisel School of Medicine at Dartmouth. She holds a PhD in cellular physiology from Michigan State University. Her research team studies viral-bacterial and polymicrobial interactions in the respiratory tract.

Reference: Zamora PF, Reidy TG, Armbruster CR, et al. Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells. PLoS Biol. 2024;22(4):e3002566. doi: 10.1371/journal.pbio.3002566