Engineering targeted pathogen killing from mixed bacterial populations

While absolutely essential to modern medicine, broad-spectrum antibiotics use has contributed to the rise in antibiotic resistance and, via perturbations of the gut microbiota, adversely impacted some aspects of human health. To address these issues, there has been recent work on the development of precision antibiotic agents that only kill pathogenic bacteria.

López-Igual et al. describe an engineered toxin-intein antimicrobial that is only activated in the presence of specific transcription factors unique to the targeted pathogen. In their paper, they demonstrate killing of an antibiotic-resistant strain of Vibrio cholerae using this method and note the potential for their approach to reduce the occurrence of antibiotic resistance.

At journal club we will be discussing:

a) briefly and broadly, the need for precision antibiotic agents and issues with various approaches to providing such therapy (e.g. novel small molecules, phages, etc.)

b) how do the authors target specific pathogens and how effective is it?

c) can we apply similar engineering approaches to modulate the microbiota in other ways?

The final human microbiome journal club of 2019 will be on December 6 at 3PM in MUMC4N55A. All are welcome!

Paper citation: López-Igual, R., Bernal-Bayard, J., Rodríguez-Patón, A., Ghigo, J. M. & Mazel, D. Engineered toxin–intein antimicrobials can selectively target and kill antibiotic-resistant bacteria in mixed populations. Nat. Biotechnol. (2019). doi:10.1038/s41587-019-0105-3

What is a microbial population and why it’s essential to estimate the horizontal gene flow?

Please join us on Friday, September 27th, 2019 at 3 pm in HSC 3N10 to discuss a new method to estimate gene flow between microbial genomes and the importance of these events in the definition of a microbial population. Arevalo et al. 2019 applied this approach, and they showed that the human commensal bacterium Ruminococcus gnavus split up into entirely different populations that show different associations with health and disease. This approach potentially allows us to study bacterial and archaeal genomes using classic evolutionary theories that are developed for plants and animals.

https://www.sciencedirect.com/science/article/pii/S0092867419307366

 

Working group has a new location

Due to the popularity of last week’s working group we will move to HSC 3N27H for the rest of the term. The new poster is here if you’d like to print and post it for your colleagues.

See you there!

 

Working group this term is moving to Fridays!

The Human Microbiome Working Group will continue this fall on Fridays at 1:30 pm in the Farncombe atrium. If there is an even in that room we can meet in the conference room instead. No need to sign up, just bring your computer and questions.

Please also feel free to download this microbiomeWG_posterF2019 poster and put it up in your lab or work area.

Cheers,

Jen

The Cystic Fibrosis Rapid Response – Translating ‘Omics data to Clinically Relevant Information

Cystic fibrosis pulmonary exacerbations (CFPEs) compound the severity of pulmonary function decline that leads to 90% of CF patient mortalities. Determining the microbial drivers of CFPEs represents a key step towards preventing and treating exacerbations. Standard methods for treating CFPEs utilize broad-spectrum antimicrobial therapy to target conventional pathogens such as P. aeruginosa. In addition to the conventional pathogens, CF infections are influenced by diverse microorganisms, rendering them polymicrobial in nature. The rapid establishment of next-generation sequencing techniques has enabled profiling of these communities using the ‘omics. 

In a recent study, the Forest Rohwer lab developed the Cystic Fibrosis Rapid Response (CFRR). CFRR utilizes viromics, metagenomics, metatranscriptomics, and metabolomics data to monitor the microbiomes of CF airways over the course of a CFPE. To support the use of CFRR in the clinic, the lab presented a case study of a CF patient experiencing a fatal pulmonary exacerbation. This patient’s microbiome comprised of the established pathogen P. aeruginosa in the days before his death. More interestingly, the study also identified E. coli as a prominent member of the CF lung during the patient’s fatal exacerbation. Using a combination of metatranscriptomics, metagenomics, and metabolomics, the study determined that this E. coli population expressed Shiga toxins that may have been released prior to the fatal exacerbation.

Overall, the study provides an example of the ways through which the ‘omics provides clinicians information to make decisions when treating CF patients. The CFRR pipeline demonstrates potential for the rapid identification of the microbes that contribute to CFPE onset.

Please join us on Friday May 24^th 2019 in HSC 3N10A to discuss the findings of this paper and the following:

1. Evaluate a case study for using the ‘omics within clinical contexts
2. Identify possible gaps and strategies towards translating ‘omics data for treating pulmonary disease

Evolution in the microbiome – What drives long term fitness and colonization?

While the composition of the microbiome in various conditions is often the focus of studies, little is known about the evolutionary dynamics of commensurable in healthy people. Evolution in complex communities such as the gut microbiome is complex and tracking adaptive evolution in commensal bacteria can provide insight as to the important factors for long term colonization in the the gut.

In their recent paper, Zhao et al. studied adaptive mutations in Bacteroides fragilis lineages from healthy donors over time and across populations. They identified several key genes that underwent parallel evolution as well as specific lineages co-existing over time. Such parallel evolution was found both in multiple sublineages in a single donor (person specific selection) or across multiple donor (general selection). Also, an active prophage was found to be responsible for the co-evolution of twospecific sub-lineages. They also found an over representation of a specific mutation in Western populations compared to Chinese populations, indicating a population specific.

Overall, this study demonstrate how adaptive evolution tracking can be used to find important target for colonization which has implication in various microbiome related fields such as microbiome manipulation, therapies and probiotics.

Please join us on Friday April 26th, 2019 at 3:00PM in HSC 3N10A to discuss the findings presented in this paper.

Paper Citation: Zhao, S. et al. Adaptive Evolution within Gut Microbiomes of Healthy People. Cell Host & Microbe (2019). doi:10.1016/j.chom.2019.03.007

 

The Human Milk Microbiota – What factors impact its composition?

Breast milk is a primary source of nutrition for infants in their first months and plays a large role in shaping the infant gut microbiota. However, the composition and determinants of the milk microbiota are not well understood.  In their recent work,  Moossavi et al. examined factors that influence the microbial content of breast milk. They studied data from 393 mother–baby pairs, where some mothers exclusively nursed their infants at the breast and others used a mechanical breast pump to collect milk. They identified mode of breastfeeding as a key determinant of milk microbiota composition and determined that milk microbiota variability is affected by maternal factors and other milk components. Additionally, their work supports the retrograde inoculation hypothesis, where the bacteria present in the infant’s oral cavity impacts the composition of the milk microbiota. Overall, the results presented in their work help elucidate features of the human milk microbiota composition, which could have potential implications for infant health.

 

Please join us on Friday March 22nd, 2019 at 3:00PM in HSC 3N10A to discuss the findings presented in this paper.

Paper Citation: Moossavi, S., Sepehri, S., Robertson, B., Bode, L., Goruk, S., Field, C. J., … & Turvey, S. E. (2019). Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors. Cell host & microbe, 25(2), 324-335.

The respiratory microbiome and susceptibility to influenza virus infection

The burden of influenza is a complex problem and has been long recognized as a significant cause of morbidity and mortality in human populations. A crippling 3500 deaths in Canada are estimated to be caused by influenza, with approximately 10 billion dollars being the consequent economic burden.  This has lead to the subsequent development of vaccines in order to reduce resulting health and economic burdens. There is overwhelming evidence indicating that the influenza virus infection leads to acute infection both in the upper and lower respiratory tracts. Unsurprisingly, there are a plethora of factors that influence one’s susceptibility to the virus.

In this paper by Lee et.al, data from a longitudinal household transmission study and proceeding generalized linear mixed effects models were used in order to study the influences of the nose and throat microbiota and the susceptibility to influenza infection. Untargeted 16S rRNA taxonomic screening was conducted to determine bacterial community “state types” concluding that it was associated with lower susceptibility to influenza virus infection. The study also demonstrates a strong association between age and the prevalence and stability of the nose/throat bacterial communities.

Please join us on Friday February 22nd, 2019 at 3:00PM in HSC 3N10A to examine the findings of this paper and discuss:

1. The relationship between the nose/throat microbiota and the flu
2. How the flu alters the bacterial community

Citation: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207898

Panning for Gold: 150,000 Genomes from Metagenomes. How’d they do it and what does it mean?

There is still debate among scientists about whether or not to publicly release their painstakingly collected  data once the main analysis is complete. Opinion on either side can get heated with major repercussions for the community at large. Luckily, many groups are able to deposit their raw sequencing data and as such, reams of metagenomic data are now publicly available from many human body sites from people around the world. Savvy computational biologists and bioinformaticians are making great use of that data to generate tools and resources that help us all.

This week we’ll discuss a microbiome paper that was published  as a Cell press Resource. The computation labs of Nicola Segata and Curtis Huttenhower teamed up with Maria Carmen Collado, Xochitl Morgan and Chris Quince for the Hurculean task of mining 10,000 human metagenomes to reconstruct as many bacterial and archaeal genomes as they could. You can find the paper here: https://www.sciencedirect.com/science/article/pii/S0092867419300017.

The paper itself is too long to analyse fully but I will go over questions like:

• What methods did they use?
• What did they uncover?
• How does this resource add to our research?

Journal club will be held January 25th at 3pm in MUMC 3N10A. No need to read the whole paper or be an expert in metagenomics to contribute, all are welcome!

The new Journal Club schedule is up

See the Journal Club page for the 2019 schedule of speakers. As usual the topics are posted the week before we meet to stay tuned and see you next year!