Bacteria Living Without Phages?
by Merry Youle
Are there environments where there are abundant bacteria and no phages? Sounds like one of our Talmudic Questions, but this one has a specific answer, and that answer is Yes. That environment was found within a cystic fibrosis (CF) lung.
This story comes from a pair of papers recently published by a group of microbial ecologists reporting their survey of the microbes and DNA viruses present in the lungs of two late-stage CF patients. Previous studies had all relied on sampled sputum or bronchial alveolar lavage fluid. These researchers instead took advantage of the opportunity to investigate the explant lungs from a CF patient who received a lung transplant. They dissected the lungs, isolated the microbes and viruses separately from each lobe, and then extracted the DNA. This approach enabled them to determine not only the diversity within each lobe, but also to ask whether each lobe housed its own distinctive community.
Because CT scans are able to detect even very small nodules in and plugging of the lung, LDCT of the chest is especially effective for diagnosing lung cancer at its earliest stage and airway plugging caused by CF. Source
Their analyses yielded several interesting findings, but the one that caught my attention most concerned the upper lobes. For most environments, it is common to find five to ten viruses (mostly phages) for every microbial cell (mostly bacteria), and high viral diversity, but these lobes with their rampant microbial community had no detectable phages. To the best of my knowledge, this is the first report of such a circumstance. But then again, these lobes aren't your typical environment. They were the site of the most severe disease in this patient and exhibited extensive mucus plugging of the airways and bronchiectatic changes. While each of the other lobes housed ~102 viral genotypes including phages that infect key CF pathogens (Pseudomonas spp., Burkholderia spp, and Staphylococcus spp.), only 3 viral genotypes were found in these lobes and none of them were phage.
What might be going on? Pseudomonas and Burkholderia live in CF lungs ensconced within biofilms of their own making. Their mucoid polysaccharide matrix provides protection against the host immune response and complicates antibiotic treatment. The authors postulate that these same barriers, most evident in the upper lobes of the transplant patient, effectively shield the bacteria from phage predation – ergo, no phages found there. With the spread of CF pathogens with multiple antibiotic resistance, there is active exploration of the possible efficacy of inhalation phage therapy. Could phages introduced by inhalation therapy fare any better? The presence of phages in the less obstructed lobes of these lungs suggests yes, at least during earlier stages of the disease before the bacteria have built such extensive barricades.
The message for the bacteria? If you can't run, you can still hide.
Reference
Willner D, Haynes MR, Furlan M, Hanson N, Kirby B, Lim YW, Rainey PB, Schmieder R, Youle M, Conrad D, Rohwer F. (2011). Case studies of the spatial heterogeneity of DNA viruses in the cystic fibrosis lung. American Journal of Respiratory Cell and Molecular Biology. PMID 21980056
It's possible all the cells of Pseudomonas aeruginosa (Pa) in these occluded lobes are descendants of one strain selected for mucoidy by lysogenic conversion. This single clone would belong to a single phage immunity group which would abort continued lysogenic cycles and hence no free phage. I suspect that these bacteria contain just one temperate phage that has the ability to select for or convert to mucoidy other isolates of Pa. Please see: R.V. Miller and V.J. Renta Rubero. Mucoid Conversion by Phages of Pseudomnas aeruginosa Strains from Patients with Cystic Fibrosis. J. Clin. Microbiol. 19:717–719 (1984). Phage therapy would have to consider phage less likely to convert cells to mucoidy and from different immunity groups.
Merry replies: Good point! The same authors had published a survey of the microbial communities in these lobes and I had checked there earlier for any hints of prophages. There are a growing number of environments known now where temperate phages predominate. But their microbial sruvey was based on 16S amplicons only, with no other genomic sequencing. You tied all this together into a possible scenario. I do hope some researchers are looking in those directions.
Seems Phage therapy could make its long deserved comeback hopefully in a few years.
Merry replies: Phage therapy for CF is definitely an active area of research now. One tact is to use phages with enhanced capabilities to digest the polysaccharides in the biofilms, thus giving them easier access to the lurking bacteria.
Very interesting and proof again of the power that Quorum Sensing in bacteria holds, not only in allowing the structure of the biofilm to decrease the effectiveness of antibiotic therapy but also to inhibit the natural bacteria killer ‑Phage!!
I wonder if future treatments might combine perhaps Phage Therapy and QS drenching analogs??
Merry replies: That sounds like a good strategy, Lynda. If we could inhibit biofilm production using analogs to disrupt the bacterial quorum sensing, then the phage might be able to help us in controlling the resilient CF pathogens. Phage therapy could give us more phage on our side, phages specific for the CF pathogens.