The clinical use of bacteriophage as an alternative to antibiotics for common infections has been explored and developed, however very little research has been carried out for mycobacteria.
Mycobacterial infections are responsible for some of the most deadly and difficult to control infections in humans and animals. Tuberculosis (TB) infects 10 million people a year and resistance is growing against the most widely used treatments. Detection is problematic as the causal pathogen, Mycobacteria tuberculosis, is difficult to detect and can lie dormant in the host.
A major problem with many of the current diagnostics is they use the host immune response to diagnose infection. A key feature of mycobacteria is their ability to avoid the host’s immune system, and this can result in immunologically based diagnostics providing inconsistent detection of infected individuals. The alternative, gold-standard, diagnostic is culture, butthis is also difficult as M. tuberculosis can take up to 12 weeks to culture.
So, a rapid, sensitive, alternative approach is required to understand, control and eradicate TB.
Historically, Phage-based diagnostics have focussed on two areas: phage amplified biologically (PhAB) assays and phage reporter assays (PRAs). One limitation of PhAB is the high rate of contaminated results, although the test does have cost-benefits. The latter, PRAs, can offer high sensitivity and specificity but the diagnostics are more expensive and efforts to commercialise the technology have been discontinued.
The review focusses on less explored emerging phage-based diagnostics that are showing promising results, and the researchers comment that more standardised reference tests would improve confidence when comparing results, calling for more studies to directly compare emerging diagnostics against the full range of existing tests, including culture, GeneXpert and sputum smear microscopy.
The review identifies two promising technologies: ‘Actiphage’ and ‘phagomagnetic separation’, with the former providing the lowest reported limit of detection for TB at <10 cells/ml*. These two methods target the mycobacterial insertion sequence DNA with PCR, showing this to be a good target for accurate diagnosis, offering high sensitivity and specificity.
Other methods are also reviewed include using enzymes to catalyse the generation of biomarkers, and the use of reporter phage.
Currently few phage-diagnostics have been translated into commercial and clinical use, and the researchers call for more studies with clinical samples as this would enable direct comparison with standard methods and enable evaluation of capability in a high-volume, real-world setting.
The review also looks at the use of bacteriophages for treatment of mycobacterial infections.
Authors reference the first clinical use of phage treatment against drug-resistant mycobacteria; a 15-year-old patient suffering from cystic fibrosis, who had a double lung transplant and persistent disseminated infection. After 6 weeks of phage treatment, complete resolution of an infected liver node was seen, along with an increase in the patient’s weight and lung function***.
The authors end with a note of caution. If both phage-therapy and phage-diagnostics become more prevalent, then care is needed to prevent resistance emerging. Consideration should be given from the outset of the type of phage employed to conserve the treatment options.
Lead author Christopher Shield concludes: “Our review reveals that bacteriophage offers a promising alternative option for the treatment and diagnosis of mycobacterial infections. However, further research and trials are needed, particularly within a clinical setting. This would enable direct comparison of phage-based diagnostics with conventional techniques.”
*Shield, C.G.; Swift, B.M.C.; McHugh, T.D.; Dedrick, R.M.; Hatfull, G.F.; Satta, G. Application of Bacteriophages for Mycobacterial Infections, from Diagnosis to Treatment. Microorganisms 2021, 9, 2366. https://doi.org/10.3390/microorganisms9112366
** Swift, B.M.C.; Meade, N.; Barron, E.S.; Bennett, M.; Perehenic, T.; Hughes, V.; Stevenson, K.; Rees, C.E.D. The development and use of Actiphage to detect viable mycobacteria from bovine tuberculosis and Johne’s disease-infected animals. Microb. Biotechnol.2020, 13, 738–746.
***Dedrick, R.M., Guerrero-Bustamante, C.A., Garlena, R.A. et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25, 730–733 (2019). https://doi.org/10.1038/s41591-019-0437-z