Adjunctive TNF Inhibition with Standard Treatment Enhances Bacterial Clearance in a Murine Model of Necrotic TB Granulomas

Abstract

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-α)–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. 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-α 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. This study provides proof-of-principle that modulation of TNF-α activity can hasten bacterial clearance during standard multi-drug TB treatment. Oral agents that modulate TNF-α 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-α inhibitors are used for TB treatment in humans.