title: Photoinactivation of Mycobacteria in vitro and in a new murine model of localized Mycobacterium bovis BCG-induced granulomatous infection.
abstract: Treatment of tuberculosis is currently hindered by prolonged antibiotic regimens and the emergence of significant drug resistance. Alternatives and adjuncts to standard antimycobacterial agents are needed. We propose that a direct attack utilizing photosensitizers and light-based treatments may be effective in curtailing Mycobacterium tuberculosis in discrete anatomical sites in the most infectious phase of pulmonary tuberculosis. To demonstrate experimental proof of principle, we have applied established photodynamic therapy (PDT) technology to in vitro cultures and an in vivo mouse model using Mycobacterium bovis BCG. We report here in vitro and in vivo PDT efficacy studies and the use of a three-dimensional collagen gel as a delivery vehicle for BCG, subcutaneously inserted, to induce specifically localized granuloma-like lesions in mice. When a benzoporphyrin derivative was utilized as the photosensitive agent, exposure to light killed extracellular and intracellular BCG in significant numbers. Collagen scaffolds containing BCG inserted in situ in BALB/c mice for 3 months mimicked granulomatous lesions and demonstrated a marked cellular infiltration upon histological examination, with evidence of caseating necrosis and fibrous capsule formation. When 10(5) BCG were present in the in vivo-induced granulomas, a significant reduction in viable mycobacterial cells was demonstrated in PDT-treated granulomas compared to those of controls. We conclude that PDT has potential in the treatment of localized mycobacterial infections, such as pulmonary granulomas and cavities.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, BAR 314, 40 Blossom Street, Boston, MA 02114, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: O'Riordan
authors.forename: David S
authors.initials: DS
authors.lastname: Sharlin
authors.forename: Jerome
authors.initials: J
authors.lastname: Gross
authors.forename: Sung
authors.initials: S
authors.lastname: Chang
authors.forename: Divya
authors.initials: D
authors.lastname: Errabelli
authors.forename: Oleg E
authors.initials: OE
authors.lastname: Akilov
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kosaka
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nau
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000008:administration & dosage; D004195:Disease Models, Animal; D005453:Fluorescence; D006099:Granuloma / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D020007:Implants, Experimental; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009164:Mycobacterium Infections / Q000188:drug therapy / Q000276:immunology; D009163:Mycobacterium bovis / Q000187:drug effects / Q000276:immunology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology; D013710:Tendons / Q000737:chemistry; D014376:Tuberculosis / Q000188:drug therapy*; D000077362:Verteporfin
chemical_list: D001500:BCG Vaccine; D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D003094:Collagen