A central paradox of tuberculosis immunity is that reinfection and bacterial persistence occur despite vigorous host immune responses concentrated in granulomas, which are organized structures that form in response to infection. Prevailing models attribute reinfection and persistence to bacterial avoidance of host immunity via establishment of infection outside primary granulomas. Alternatively, persistence is attributed to a gradual bacterial adaptation to evolving host immune responses. We show here that superinfecting Mycobacterium marinum traffic rapidly into preexisting granulomas, including their caseous (necrotic) centers, through specific mycobacterium-directed and host cell–mediated processes, yet adapt quickly to persist long term therein. These findings demonstrate a failure of established granulomas, concentrated foci of activated macrophages and antigen-specific immune effector cells, to eradicate newly deposited mycobacteria not previously exposed to host responses.
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We thank K. Klein for technical assistance; K. Klein and P. Carroll for constructing plasmids; K. Urdahl, S. Miller, D. Sherman, M. Kaja, C. Wilson, M. Bevan and N. Salama for discussions; A. Farr and J. Dooley for tissue cryosectioning advice and equipment; D. Lauman for advice on statistics; and K. Urdahl, M. Kaja, T. Pozos and D. Tobin for comments on the manuscript. Supported by National Institutes of Health (R01 AI 36396) and an Ellison Medical Foundation New Scholar in Global Infectious Diseases award (L.R.).
The authors declare no competing financial interests.
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Cosma, C., Humbert, O. & Ramakrishnan, L. Superinfecting mycobacteria home to established tuberculous granulomas. Nat Immunol 5, 828–835 (2004) doi:10.1038/ni1091
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