Journal
PLOS ONE
Volume 7, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0039680
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Funding
- National Institutes of Health [OD006492]
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Background: It has been hypothesized that early host-responses during TB treatment may paradoxically promote survival of persistent bacteria. We therefore evaluated whether adjunctive inhibition of tumor necrosis factor alpha (TNF-alpha)-a key cytokine in host responses against TB-could hasten bacterial clearance in a mouse strain that develops necrotic lesions in response to Mycobacterium tuberculosis infection. Methodology/Principal Findings: Six weeks after an aerosol infection, C3HeB/FeJ mice received standard TB treatment with or without adjunctive TNF inhibition (etanercept for the initial six weeks). Functional TNF-alpha levels and lung pathology were found to be reduced in the mice receiving etanercept. Compared to standard TB treatment, the addition of etanercept resulted in a significantly lower pulmonary bacterial burden, corresponding to the phase when a significant proportion of bacteria are multiplying slowly (p<0.0233). Finally, only 10.5% of mice receiving adjunctive etanercept versus 27.8% receiving standard TB treatment alone relapsed. Conclusion: This study provides proof-of-principle that modulation of TNF-alpha activity can hasten bacterial clearance during standard multi-drug TB treatment. Oral agents that modulate TNF-alpha should therefore be considered as adjunct therapies for shortening TB treatments. However, due to concerns of reactivation disease, additional studies need to be performed before TNF-alpha inhibitors are used for TB treatment in humans.
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