Phage Therapy Is Effective against Infection by Mycobacterium ulcerans in a Murine Footpad Model

Abstract

BackgroundBuruli Ulcer (BU) is a neglected, necrotizing skin disease caused by Mycobacterium ulcerans. Currently, there is no vaccine against M. ulcerans infection. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages is still based on the surgical resection of infected skin. The use of bacteriophages for the control of bacterial infections has been considered as an alternative or to be used in association with antibiotherapy. Additionally, the mycobacteriophage D29 has previously been shown to display lytic activity against M. ulcerans isolates.Methodology/Principal findingsWe used the mouse footpad model of M. ulcerans infection to evaluate the therapeutic efficacy of treatment with mycobacteriophage D29. Analyses of macroscopic lesions, bacterial burdens, histology and cytokine production were performed in both M. ulcerans-infected footpads and draining lymph nodes (DLN). We have demonstrated that a single subcutaneous injection of the mycobacteriophage D29, administered 33 days after bacterial challenge, was sufficient to decrease pathology and to prevent ulceration. This protection resulted in a significant reduction of M. ulcerans numbers accompanied by an increase of cytokine levels (including IFN-γ), both in footpads and DLN. Additionally, mycobacteriophage D29 treatment induced a cellular infiltrate of a lymphocytic/macrophagic profile.Conclusions/SignificanceOur observations demonstrate the potential of phage therapy against M. ulcerans infection, paving the way for future studies aiming at the development of novel phage-related therapeutic approaches against BU.

Transient Contacts on the Exterior of the HK97 Procapsid That Are Essential for Capsid Assembly

“…The HK97 fold has been detected in every tailed phage capsid that has been imaged at sufficient resolution, including P22 11; 12; 13 , T4 14 , λ 15 , ϕ29 16 , T5 17; 18 , P2/P4 19 , epsilon15 20 , T7 21; 22 , the tailed-phage-like archaevirus HSTV-1 23 , in the base layer of the Herpesvirus (HSV1) major capsid protein 24 and in the bacterial comparments known as encapsulins 25 . With renewed interest in phage therapy to combat multiple-drug-resistant bacterial pathogens 26; 27; 28 , and an emerging interest in using bacteriophage capsids as platforms for nanotechnology 29 (http://www.nano.gov/) directed to the treatment of disease 30; 31 and the creation of new technologies 32; 33; 34; 35 , it is important to have a deep understanding of capsid structures and assembly pathways in order that they can be manipulated and utilized to the greatest extent.…”

Dynamics of Mycobacteriophage-Mycobacterial Host Interaction: Evidence for Secondary Mechanisms for Host Lethality

“…The major reason behind this is that the bacteria can transit into a dormant state and remain as a latent infection within the body. This latent form of the bacteria is not acted upon by most drugs, making it difficult to eradicate the disease (20)(21)(22). Phages for mycobacteria were reported more than 7 decades ago (23,24).…”

“…Methods to kill M. tuberculosis using mycobacteriophages already have been explored using the lytic mycobacteriophage TM4, which was introduced into a macrophage cell line harboring M. tuberculosis using M. smegmatis as a carrier, resulting in the reduction of pathogen counts (57,58). Phage D29, the model system used in this study, has been found to be effective against Mycobacterium ulcerans in a murine footpad model (22). It is possible that some of the ameliorative effects of phage treatment observed in these studies are due to the enhanced release of superoxides, which, as mentioned above, can act in trans not only on the bacteria producing them but also on the bystanders.…”

Theranostic applications of phage display to control leishmaniasis: selection of biomarkers for serodiagnostics, vaccination, and immunotherapy

“…The treatment with D29 mimotope also stimulated the increase in infi ltrating lymphocytes and macrophages. The study has demonstrated a potential of phage-based therapy against M. ulcerans infection, paving the way for the development of novel phage-based therapeutic approaches (45) . Phage-displayed peptides employed as vaccine candidates have two important advantages.…”