Host-Directed Therapies: Modulating Inflammation to Treat Tuberculosis

Abstract

Following infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy.

Keywords: MDSCs; MMPs (metalloproteinases); PARP inhibition (PARPi); diphtheria fusion protein toxin; host-directed therapies; immunotherapy; tuberculosis.

Figure 1

Both pro- and ani-inflammatory responses play critical roles in TB pathogenesis. (Left) Proinflammatory responses and tissue remodeling in TB are important for bacterial clearance but may lead to excessive inflammation and persisting lung damage. Adjunct modulation of lung remodeling (for example, via TNFα or MMP inhibition) or inflammation (for example, by corticosteroids) may improve the outcome of TB therapy. Inhibition of PARP1, an essential NF-κB, TNFα and MMP cofactor and driver of lung inflammation, may be similarly beneficial. (Right) Anti-inflammatory responses safeguard against tissue damage but may result in less than desirable bacterial clearance. These responses are often mediated by immunosuppressive cell populations, such as MDSCs, Tregs and M2 macrophages. Inhibition or elimination of these cell types may be achieved using the inhibitors shown. This figure was created using BioRender.