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.
Highlights
Tuberculosis (TB) is a devastating communicable disease caused by Mycobacterium tuberculosis (M.tb) that is responsible for approximately 10 million infections and 1.4 million human deaths every year [1]
While extracellular matrix remodeling is important for immune cell migration and granuloma formation, 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
While tumor necrosis factor a (TNFa) antagonists have the potential to improve TB therapy when used as adjunctive agents, there have been concerns about their expense, their need to be given parenterally, and the potential for disease worsening if administered without adequate anti-TB chemotherapy, and due to these concerns advanced clinical trials to test them as adjunctive host-directed therapies (HDTs) for TB have not been performed [18, 60, 67]
Summary
Tuberculosis (TB) is a devastating communicable disease caused by Mycobacterium tuberculosis (M.tb) that is responsible for approximately 10 million infections and 1.4 million human deaths every year [1]. In individuals who progress to active TB, granulomatous containment breaks down, resulting in lesion expansion, necrosis and liquefaction accompanied by bacterial proliferation and lung damage [2]. This granulomatous inflammation during active TB may permanently diminish lung function even after completion of TB therapy [3]. The host utilizes both anti- and pro-inflammatory mechanisms in an effort to contain the infection: during latent M.tb infection, the immune response is successfully balanced but during active disease, this homeostatic balance is lost and disease progression occurs. We discuss several classes of HDTs that may reduce nonproductive inflammation and PTLD (Figure 1, left; Table 1, top)
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