title: PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis.
abstract: Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. Among those with latent tuberculosis, it is now recognized that there is also a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. Here, functional imaging with 18F-fluorodeoxygluose positron emission tomography and computed tomography (PET CT) of cynomolgus macaques with latent M. tuberculosis infection was used to characterize the features of reactivation after tumor necrosis factor (TNF) neutralization and determine which imaging characteristics before TNF neutralization distinguish reactivation risk. PET CT was performed on latently infected macaques (n = 26) before and during the course of TNF neutralization and a separate set of latently infected controls (n = 25). Reactivation occurred in 50% of the latently infected animals receiving TNF neutralizing antibody defined as development of at least one new granuloma in adjacent or distant locations including extrapulmonary sites. Increased lung inflammation measured by PET and the presence of extrapulmonary involvement before TNF neutralization predicted reactivation with 92% sensitivity and specificity. To define the biologic features associated with risk of reactivation, we used these PET CT parameters to identify latently infected animals at high risk for reactivation. High risk animals had higher cumulative lung bacterial burden and higher maximum lesional bacterial burdens, and more T cells producing IL-2, IL-10 and IL-17 in lung granulomas as compared to low risk macaques. In total, these data support that risk of reactivation is associated with lung inflammation and higher bacterial burden in macaques with latent Mtb infection.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Pauline
authors.initials: P
authors.lastname: Maiello
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Gideon
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: M Teresa
authors.identifier: 0000-0002-0113-3951
authors.initials: MT
authors.lastname: Coleman
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Cadena
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rodgers
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Gregg
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: O'Malley
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jaime
authors.identifier: 0000-0002-9308-4957
authors.initials: J
authors.lastname: Tomko
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fillmore
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: L James
authors.initials: LJ
authors.lastname: Frye
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Tara
authors.initials: T
authors.lastname: Rutledge
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: DiFazio
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Janssen
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.affiliation: Department of Infectious Diseases Immunology, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Andersen
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Fortune
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007091:Image Processing, Computer-Assisted; D055985:Latent Tuberculosis / Q000000981:diagnostic imaging* / Q000382:microbiology* / Q000473:pathology*; D008252:Macaca fascicularis; D009169:Mycobacterium tuberculosis; D016133:Polymerase Chain Reaction; D000072078:Positron Emission Tomography Computed Tomography; D014775:Virus Activation; D017735:Virus Latency