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PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis

Lin, PL and Maiello, P and Gideon, HP and Coleman, MT and Cadena, AM and Rodgers, MA and Gregg, R and O’Malley, M and Tomko, J and Fillmore, D and Frye, LJ and Rutledge, T and DiFazio, RM and Janssen, C and Klein, E and Andersen, PL and Fortune, SM and Flynn, JAL (2016) PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis. PLoS Pathogens, 12 (7). ISSN 1553-7366

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Lin, PLpll7@pitt.eduPLL7
Maiello, P
Gideon, HP
Coleman, MT
Cadena, AMamc201@pitt.eduAMC201
Rodgers, MAmar118@pitt.eduMAR118
Gregg, R
O’Malley, M
Tomko, J
Fillmore, DDJF91@pitt.eduDJF91
Frye, LJljf19@pitt.eduLJF19
Rutledge, Ttar36@pitt.eduTAR36
DiFazio, RMrod28@pitt.eduROD28
Janssen, C
Klein, Eeklein@pitt.eduEKLEIN
Andersen, PL
Fortune, SM
Flynn, JAL
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 July 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Pathogens
Volume: 12
Number: 7
DOI or Unique Handle: 10.1371/journal.ppat.1005739
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Pediatrics
Refereed: Yes
ISSN: 1553-7366
Date Deposited: 23 Aug 2016 13:40
Last Modified: 22 Jun 2021 11:55


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