Phage Therapy Treats Resistant Lung Infection: Codon Index #49
Plus: Mitochondrial base editors cause many off-target mutations & sniffing cytomegalovirus extends mouse lifespan.
Hello. Thanks, as always, for reading.
TL;DR: A patient with cystic fibrosis and a treatment-resistant Mycobacterium abscessus infection was successfully treated with engineered bacteriophages in a major milestone for phage-based therapies. And mice that inhale cytomegalovirus vectors containing one of two genes, either telomerase reverse transcriptase or follistatin, live much longer than untreated mice.
Felix d’Herelle, microbiology extraordinaire at the Institut Pasteur in Paris, first proposed in 1917 that bacteriophages — little viruses that infect bacteria — could eradicate bacterial infections. Phage therapies swelled in popularity and were a hot topic throughout the 1920s and 1930s. The approach was supplanted by penicillin and antibiotics in the 1940s, while phage therapy reverted to a ‘backwater’ sort of science; a fringe field of study.
Its return to science in the last decade, though, has been transcendent. For a new study in Cell, a 26-year-old patient with cystic fibrosis and a treatment-resistant infection of Mycobacterium abscessus was treated with two bacteriophages that completely eradicated his infection. This paper marks a major milestone; one that could prove pivotal for treating antibiotic-resistant infections in the future.
M. abscessus bacteria grow quickly and are multidrug-resistant. This patient had been battling an M. abscessus infection for about five years before he started on the phage treatment, and “was maintained on four to five drugs” for that time, according to the study.
Researchers on this paper — led by Jerry Nick, Graham Hatfull and Rebecca Davidson at National Jewish Health in Denver, Colorado and the University of Pittsburgh — first swabbed some of the bacteria from the patient and then screened for phages that were most effective at infecting and lysing those cells. They found two phages that, either alone or in combination, could destroy the bacteria — BPsΔ33HTH_HRM10 and D29_HRMGD40.
In September 2020, the patient was intravenously injected, twice a day, with a billion plaque-forming units of the first phage and 100 million of the second phage. He was thus injected, in this way, every day through at least March 2022, without any observable side effects.
About one year after phage treatment began, the patient received a lung transplant. A bit of tissue from that excised lung was tested for M. abscessus, and no bacteria were found. The patient was tested for anti-phage antibodies — and had lots of them — but this immune response didn’t dampen the phage therapy’s effects. This paper, then, will likely become the standard-bearer for many bacteriophage therapies yet to come.
Read more at Cell.
This is a strange study. I’m not sure what to think about it.
There are so-called “protective” factors that increase longevity. A protein called telomerase reverse transcriptase, or TERT, maintains telomere ends on chromosomes by adding a TTAGGG repeat. More TERT expression is typically correlated with a longer lifespan. Follistatin, a protein that binds to proteins in the TGF-β pathway, is another such protective factor.
For this study, researchers packaged a gene encoding the TERT or follistatin proteins inside of a cytomegalovirus vector, and shot those viruses into mice. Mice that inhaled or were injected with the TERT lived 41.4 percent (median value) longer than untreated animals. Mice that inhaled the follistatin lived 32.5 percent longer. Injected and inhaled modalities worked equally well.
TERT expression, the researchers found, peaked around 7 days post-injection or post-inhalation. Each virus was tested on nine female mice, and treatments started ebgan at 18 months of age (which is quite old for a mouse). Animals either received a mock injection (saline), inhaled empty cytomegalovirus, were injected with empty cytomegalovirus, or else were injected (or inhaled) cytomegalovirus packed with TERT or follistatin. Considering that the treatments began at 18 months of age in the mice, the survival curves seem extremely remarkable.
I’m excited to see how this study will be extended. Would other viral vectors work equally well, or is there some inherent property of cytomegalovirus that help them to prolong lifespan?
Read more at PNAS.
(↑ = recommended article, * = open access, † = review article, )
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