| Host specificity |
Global phage database screening. Phage’s host range expansion using directed phage evolution and/or bioengineering. Development of screening bioinformatics tools to identify targeted M.tb host virulent factor epitopes (e.g., efflux pump).
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| Unknown impact of human ALF on the M.tb cell envelope |
• Identify how the M.tb cell envelope adapts (changes) to the different environments that encounters at different stages of infection [e.g., contact with ALF, within the phagosome, extracellular, within granulomas or cavities, or when being transmitted (in sputum)]. |
| Phages access to intracellular M.tb
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Novel phage delivery systems [e.g., M. smegmatis (Trojan horse concept), phage microencapsulation]. Phage bioengineering to recognize well-defined macrophage receptors (the mannose receptor or MR).
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M.tb resistance to phages |
Use of different phage cocktails. Phage-drug combined treatment (phage-drug synergy) in combination with the mammalian host immune response. Phage sequential treatment. Phage personalized treatment.
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| Overactivation of the mammalian host immune system and risk of anaphylaxis |
Optimize phage delivery routes. Establish phage dosage and frequency. Maximize synergy between phages and the mammalian host immune system.
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| Lack of phage therapy regulations |
• Standardize global regulations for phage production (under GMP conditions). |
| Phage cytotoxicity to the human host |
Use of highly lytic phages that do not integrate into the M.tb genome. Targeted phage genetic bioengineering to remove potential phage virulent factors to the mammalian host. Define function of unknown phage genes.
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