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

Abstract

BackgroundIt 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.Methodology/Principal FindingsSix 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.ConclusionThis 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.

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

“…Hence, blocking the activity of TNF-α has been explored as a potential hostdirected therapy for TB. Treatment of Kramnik mice with a TNF-α inhibitor etanercept or enbrel in conjunction with standard TB treatment reduced pulmonary bacterial burden and ameliorated lung pathology [58,59]. The key role of TNF-α in TB pathogenesis is highlighted by the increased risk of TB reactivation in patients receiving TNF-α inhibitors [7,58,59].…”

“…Treatment of Kramnik mice with a TNF-α inhibitor etanercept or enbrel in conjunction with standard TB treatment reduced pulmonary bacterial burden and ameliorated lung pathology [58,59]. The key role of TNF-α in TB pathogenesis is highlighted by the increased risk of TB reactivation in patients receiving TNF-α inhibitors [7,58,59]. However, a clinical trial in HIV patients with pulmonary TB where TNF-α was administered in combination with anti-TB drugs, reported an improved response to TB treatment without major side effects [59].…”

Exploring the potential of adjunct therapy in tuberculosis

“…We propose that it is important that TNF-a inhibitors need to be tested in combination with TB drugs, as the latter may have effects on the host response, in addition to antimycobacterial effects as reported for pyrazinamide and INH [71,72]. Interestingly, the TNF-a inhibitor etanercept in combination with first-line drugs reduced bacterial load [29].…”

“…Risk of reactivation is higher with antibody-based therapy such as infliximab and adalimumab as compared to etanercept, a soluble TNF-a inhibitor [27,28]. Significantly, when etanercept was used as adjunct to standard TB treatment in C3HeB/FeJ mice that develop necrotic granulomas, increased bacterial clearance was reported and a lower relapse rate was seen in mice treated with etanercept as compared to standard therapy [29]. Therapeutic approaches that augment the microbicidal activity of TNF-a on mycobacteria and not the necrosis of macrophages, are likely to overcome the adverse effects of inhibiting pleiotropic cytokines like TNF-a [26].…”

Novel Adjunctive Therapies for the Treatment of Tuberculosis

“…Although the granuloma is believed to constitute a host defense mechanism, it may benefit the pathogen by presenting a physical barrier against both the immune response and the antimicrobial therapy [64]. Moreover, central necrosis of the granuloma, leading to caseation, is also driven by TNF-α, and may provide a unique microenvironment that promotes bacterial survival and persistence [65]. A recent review details the molecular mechanisms of TNF-α mediated tissue damage.…”