Robert W Gregg1, Pauline Maiello2, H Jacob Borish2, M Teresa Coleman2, Douglas S Reed3, Alexander G White2, JoAnne L Flynn2, Philana Ling Lin4. 1. Department of Chemical Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA. 2. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 3. Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA. 4. Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Abstract
BACKGROUND: Little is known about granuloma progression of Mycobacterium tuberculosis infection in humans. Using serial positron emission tomography and computed tomography (PET/CT) of an animal model that recapitulates human infection with M. tuberculosis, we are able to track lung granulomas. OBJECTIVE: We characterized the spatial and temporal pattern of granuloma formation during primary infection and reactivation. METHODS: Serial PET/CT was performed on cynomolgus macaques (n = 28) during primary and reactivation M. tuberculosis infection. Distances between granulomas during the first six weeks post infection ("primary" granulomas) were compared to new granulomas that developed afterwards ("secondary" granulomas) using nearest neighbor analysis during primary infection, reactivation and between different routes of infection. RESULTS: Secondary granulomas developed within 2 cm of a primary granuloma within the same lung lobe with 80% probability during the course of primary infection, and this same pattern was observed during reactivation of latent infection after immune suppression. Using a logistic growth function, we were able to predict the maximum number of granulomas that would develop over the course of infection with good correlation (R2 = 0.96). CONCLUSION: These data provide important insights into the dynamic patterns of bacterial dissemination during the earliest phases of primary infection and reactivation tuberculosis.
BACKGROUND: Little is known about granuloma progression of Mycobacterium tuberculosis infection in humans. Using serial positron emission tomography and computed tomography (PET/CT) of an animal model that recapitulates human infection with M. tuberculosis, we are able to track lung granulomas. OBJECTIVE: We characterized the spatial and temporal pattern of granuloma formation during primary infection and reactivation. METHODS: Serial PET/CT was performed on cynomolgus macaques (n = 28) during primary and reactivation M. tuberculosis infection. Distances between granulomas during the first six weeks post infection ("primary" granulomas) were compared to new granulomas that developed afterwards ("secondary" granulomas) using nearest neighbor analysis during primary infection, reactivation and between different routes of infection. RESULTS: Secondary granulomas developed within 2 cm of a primary granuloma within the same lung lobe with 80% probability during the course of primary infection, and this same pattern was observed during reactivation of latent infection after immune suppression. Using a logistic growth function, we were able to predict the maximum number of granulomas that would develop over the course of infection with good correlation (R2 = 0.96). CONCLUSION: These data provide important insights into the dynamic patterns of bacterial dissemination during the earliest phases of primary infection and reactivation tuberculosis.
Authors: Philana Ling Lin; Teresa Coleman; Jonathan P J Carney; Brian J Lopresti; Jaime Tomko; Dan Fillmore; Veronique Dartois; Charles Scanga; L James Frye; Christopher Janssen; Edwin Klein; Clifton E Barry; JoAnne L Flynn Journal: Antimicrob Agents Chemother Date: 2013-06-24 Impact factor: 5.191
Authors: Alexander G White; Pauline Maiello; M Teresa Coleman; Jaime A Tomko; L James Frye; Charles A Scanga; Philana Ling Lin; JoAnne L Flynn Journal: J Vis Exp Date: 2017-09-05 Impact factor: 1.355
Authors: I Bukreeva; G Campi; M Fratini; R Spanò; D Bucci; G Battaglia; F Giove; A Bravin; A Uccelli; C Venturi; M Mastrogiacomo; A Cedola Journal: Sci Rep Date: 2017-01-23 Impact factor: 4.379
Authors: Constance J Martin; Anthony M Cadena; Vivian W Leung; Philana Ling Lin; Pauline Maiello; Nathan Hicks; Michael R Chase; JoAnne L Flynn; Sarah M Fortune Journal: mBio Date: 2017-05-09 Impact factor: 7.867
Authors: Philana Ling Lin; Pauline Maiello; Hannah P Gideon; M Teresa Coleman; Anthony M Cadena; Mark A Rodgers; Robert Gregg; Melanie O'Malley; Jaime Tomko; Daniel Fillmore; L James Frye; Tara Rutledge; Robert M DiFazio; Christopher Janssen; Edwin Klein; Peter L Andersen; Sarah M Fortune; JoAnne L Flynn Journal: PLoS Pathog Date: 2016-07-05 Impact factor: 6.823