Transmembrane delivery of antimicrobial peptides by engineered eCIS into macrophages for intracellular mycobacteria elimination
In the authors' words
Mycobacterium tuberculosis ( M . tuberculosis , Mtb) is an intracellular bacterium persisting in macrophages, which can cause chronic infection and drug resistance. To address transmembrane limitation and improve treatment accuracy, we employed the Photorhabdus virulence cassette (PVC), a typical bacterial extracellular Contractile Injection System (eCIS), to deliver antimicrobial peptides (AMPs) into macrophages for intracellular mycobacteria clearance. We demonstrated that the survival of various intracellular mycobacteria, including Mycobacterium smegmatis ( M. smegmatis ), Mycobacterium bovis ( M. bovis ), M. tuberculosis and its isoniazid-resistant strain, can be significantly inhibited by PVC-mediated AMP transmembrane delivery. The engineered PVC, loaded with mycobacteriophage-derived AMPs and targeting alveolar macrophages (AMs) through binding to surface receptor CD11b, eliminated AM-dwelling mycobacteria and alleviated inflammation in murine infection models. Notably, the pulmonary mycobacterial load in M. tuberculosis H37Rv-infected mice was reduced by more than tenfold. In summary, this work represents a pioneering application of engineered PVC-based intracellular delivery of biomacromolecules into macrophages, providing a novel therapeutic strategy against mycobacterial infection.
Appeared: Friday, September 25. Science Advances. Peer-reviewed journal.