Superinfecting mycobacteria home to established tuberculous granulomas

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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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Figure 1: Preexisting infection confers immunity to a low-dose secondary infection.
Figure 2: Long-term superinfection of frogs results in comingling of primary and secondary infecting strains.
Figure 3: Distribution of preinfecting and superinfecting M. marinum strains in frog tissues after long-term infection.
Figure 4: Superinfecting bacteria and beads traffic into pre-established granulomas.
Figure 5: Trafficking of M. marinum versus latex beads into pre-established M. marinum granulomas.
Figure 6: S. arizonae is mostly excluded from M. marinum granulomas.
Figure 7: M. marinum traffic into caseated fish lesions.
Figure 8: Superinfecting bacteria induce granuloma-specific genes after entry into mature granulomas.


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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.).

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Correspondence to Lalita Ramakrishnan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Distribution of primary- and secondary-infecting M. marinum in frog tissues 3 days after secondary infection. (PDF 87 kb)

Supplementary Table 2

S. arizonae is no longer within established M. marinum granulomas by seven days after superinfection. (PDF 105 kb)

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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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