Phage therapy in the human gut

Issue 37 | July 18, 2019

9 min read

This week, Sabrina Green, a graduate student at Baylor College of Medicine, tells us how gut pathogens like ExPEC could be treated with phages, describes the challenges, and highlights her own research on the topic.

Also in this issue: BiomX entering the stock market, Pherecydes partnering with a not-for-profit to make phages for UTIs, Bayer launching a phage crop disease company, plenty of new job openings at Eligo, grant funds for studying human-microbe interactions, a Bacillus phage mistaken for a plasmid, and a mini phage bioinformatics Q&A for beginners.

What’s New

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BiomX, a biotech company developing natural and engineered phages to treat microbiome diseases, announced a merger agreement with Chardan Healthcare Acquisition Corp. The combined company is expected to be listed on the New York Stock Exchange under the name BiomX, and will proceed with developing BiomX’s phage products. This is a big deal for phage biotech as a field, as it means more public visibility and more funding, and importantly, it’s a signal that investors are gaining confidence in phage-based technologies.

Pherecydes Pharma is joining forces with BIOASTER, a French not-for-profit foundation that brings together academic, industry and its own capacities to execute high-impact, collaborative projects, to explore the use of phage therapy to treat complicated urinary tract infections.

Bayer has teamed up with the Israeli life sciences investment company Trendlines to form a new biotech company, Ecophage, which will develop phage-based treatments of crop diseases.

Phage surprises all around! Emma Piligrimova and colleagues at the Skryabin Institute of Biochemistry and Physiology of Microorganisms in Russia published a paper on a new Bacillus phage that was previously thought to be a plasmid, and which also appears to represent a new Siphoviridae genus.

The Burroughs-Wellcome fund has announced a grant to fund study of the interplay between human and microbial biology. The deadline is November 15, 2019. Perhaps phage researchers studying phage interactions with the microbiome/pathogens/human host could fit their research into this scope?

Latest Jobs

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Professional Research Assistant: Phage-enterococcal interactions

University of Colorado, Denver (Anschutz Medical Campus)

Dr. Breck Duerkop, Denver, Colorado

A full-time Professional Research Assistant (PRA) position is available, starting immediately, to work in the laboratory of Dr. Breck Duerkop in the Department of Immunology and Microbiology, University of Colorado School of Medicine. The Duerkop lab studies Gram-positive pathogenic enterococci, including Enterococcus faecalis and E. faecium, and the viruses that infect these bacteria known as bacteriophages. Dr. Duerkop’s group seeks to understand how bacteriophage-enterococcal interactions contribute to the pathogenesis of colonization and disease.

Patent engineer

Eligo Bioscience

Paris, France

We are looking for passionate and driven scientists with significant experience in drafting patent applications to join our international and highly motivated team in Paris working on engineered phages and CRISPR phages. The ideal candidate has experience in microbiology, phage biology and molecular biology.

In-vivo scientists / Animal model experts

Eligo Bioscience

Paris, France

We are looking for passionate and driven scientists with expertise in testing phage treatments in animals to join our international and highly motivated team in Paris working on engineered phages and CRISPR phages. The ideal candidate has strong skills in animal handling and knowledge in animal models for phage treatments.

Phage biologists / Automation enthusiasts

Eligo Bioscience

Paris, France

We are looking for passionate and driven scientists with expertise in phage biology to join our international and highly motivated team in Paris working on engineered phages and CRISPR phages. The ideal candidate loves phages, robots, discovery, and managing large amounts of data, and will become a key member of our Discovery and Automation team!

Synthetic biologists / Phage (protein) Engineers

Eligo Bioscience

Paris, France

We are looking for passionate and driven scientists with expertise in synthetic biology to join our international and highly motivated team in Paris working on next-generation tools for editing the microbiome (engineered phages, CRISPR systems, etc.). The ideal candidate can copy, paste and edit genetic code on a plasmid or a genome as easily as using Word.

Community Board

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Anyone can post a message to the phage community — and it could be anything from collaboration requests, post-doc searches, sequencing help — just ask!

Community Q&A: Database of phage genomes for mapping / favorite mapping pipeline?

Here’s a great example of the phage community helping each other out on Twitter — thanks to Stephen Stockdale of APC Microbiome (@SteveStockyPhD) and Simon Roux of the Joint Genome Institute (@simroux_virus) for providing answers!

Here’s the question:

Does anyone know of a database of (putative) phage genomes that you can map reads against? Or your favorite pipeline for mapping reads to a set of references/contigs? Bonus points if it’s easy to use for people who don’t like coding (that’s me)! — @ElysianTweets

The answers (so far):

If you are not comfortable downloading viral RefSeq, there is the complete reference viral database (RVDB) — @SteveStockyPhD

Or Andrew Millard’s group @milja001 have an easy to download database — @SteveStockyPhD

Or if you would like easy to download crAss-like phage sequences — @SteveStockyPhD

If you have access to a server that will run alignments and process output (using Bowtie2 and Samtools), but are not comfortable with coding, I can send you some commands. — @SteveStockyPhD

And for mapping reads to genomes without the need to code, we have iVirus on @CyVerseOrg, with full protocols courtesy of Ben Bolduc from @Lab_Sullivan. — @simroux_virus

If you get help from someone in the phage community, or you see an example like this, send it to [email protected] — we’d love to feature it here!

Phage therapy in the human gut

Graduate Student

Maresso Lab, Baylor College of Medicine, Houston, TX, United States, Tailor Service Center, Houston, TX, United States

Twitter @https://twitter.com/MotherOfPhage

Sabrina Green is a senior graduate student in Dr. Anthony Maresso’s lab in the department of Molecular Virology and Microbiology at Baylor College of Medicine in Houston, Texas. Her early research was on the pathogenesis of Extraintestinal pathogenic E. coli (ExPEC). Now she works to develop phage therapy to prevent gut-derived infections caused by ExPEC. She is currently the microbiome lead, social media lead and advisor for TAILΦR.

Phage Hosts

Escherichia coli

Pseudomonas aeruginosa

The gut is a very complex place. It is home to a variety of microbes, including phages. How phages interact in this vicinity is only just starting to be thoroughly characterized. This makes it an exciting time to work in this field, but also presents a challenge. Our challenge is how to use phage to only kill specific strains in the gut in order to prevent life-threatening bacterial infections.

The drug resistance problem

Multidrug resistant (MDR) strains of bacteria are infecting millions of people yearly. Many of these deadly strains are enteric—bacteria that naturally reside in the gut. By eliminating these strains from the gut, we may be able to prevent life-threatening disease as well as the spread of drug resistance.

The problem with ExPEC

My work has focused on the use of phages to treat Extraintestinal pathogenic E. coli or ExPEC. These pathogens are the number one cause of UTI and the primary cause of both neonatal meningitis and adult bacteremia. These strains are multidrug-resistant and likely responsible for the global dissemination of drug resistance. More troubling, these pathogens have been found in our companion animals, in our food, and within our own gut: the primary ExPEC reservoir.

How phages can help

Phages have the ability to kill or lyse drug-resistant strains of bacteria. They are also evolvable, and we can evolve them to lyse bacterial strains that have developed resistance to phages. The greatest benefit to using phages in the gut is phage specificity. Phages can target and lyse specific strains of bacteria while leaving the rest of the microbiota intact.

Targeting ExPEC with phages

We have been able to isolate a library of phages that target MDR ExPEC strains. Common laboratory phages do not infect these bacteria. So, most of our ExPEC-targeting phages have been isolated from known reservoirs of ExPEC, including chickens, pigeons, ducks, and dogs. Using these phages, we have been able to treat MDR bacteremia in mouse models that recapitulate ExPEC disease. However, our ultimate goal is to remove these strains from their primary reservoir to prevent disease and the dissemination of drug-resistant strains.

Phage therapy in the human gut

Since the discovery of phages, these predatory viruses have been used to treat people with intestinal bacterial infections. There are many individual accounts of their successful use in the gut.

Of the major clinical trials related to gut therapy, one is frequently mentioned and cited—the Phase I/II trial for E. coli pediatric diarrhea in Bangladesh in 2009. In this trial, hospitalized children received either a cocktail of T4 phages, a cocktail of phages directed against E. coli and Proteus species, or saline. The trial was halted due to lack of efficacy, although there were no reported adverse effects. One hypothesis proposed for the lack of efficacy was low phage titers in the gut. This may have been attributed to how it was dosed: orally, without antacid. Phages are pH-sensitive, and do not normally survive gastric transit. Also, the low titer may have been attributed to the characteristics of the pathogen within the gut. Low pathogen titer in the gut could reduce phage titer in the gut, because phages require bacteria to replicate.

What’s needed next

Before phages can be used in the gut, it is important to understand the gut environment, and to understand how the targeted pathogen colonizes this environment. Phages should be tested in model systems that can recapitulate human disease. A library of phages suited to target these pathogens within this environment is also needed. Overcoming these challenges will allow us to use phages to eliminate deadly MDR bacteria from the gut and prevent disease.