Host Targeted Activity of Pyrazinamide in Mycobacterium tuberculosis Infection

Abstract

Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). In the present study, we have used in vitro and in vivo systems to investigate whether PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. In vitro we have examined the effect of PZA on cytokine and chemokine release by Mtb-infected or Toll-like receptor (TLR) -stimulated primary human monocytes. In vivo, we have investigated at the transcriptional levels using genome-wide microarray gene expression analysis, whether PZA treatment of Mtb-infected mice alters the host immune response to Mtb infection in the lungs. Here, we report that PZA treatment of Mtb-infected human monocytes and mice significantly reduces the release of pro-inflammatory cytokines and chemokines, including IL-1β, IL-6, TNF-α and MCP-1 at the protein and at the gene transcription levels, respectively. Data from microarray analysis also reveal that PZA treatment of Mtb-infected mice significantly alters the expression level of genes involved in the regulation of the pro-inflammatory mediators, lung inflammatory response and TLR signaling networks. Specifically, genes coding for adenylate cyclase and Peroxisome-Proliferator Activated Receptor (PPAR), molecules known for their anti-inflammatory effect, were found to be up-regulated in the lungs of PZA-treated Mtb-infected mice. Based on the microarray findings, we propose that PZA treatment modulates the host immune response to Mtb infection by reducing pro-inflammatory cytokine production, probably through PPAR- and NF-kB- dependent pathways. In addition, our results suggest that inclusion or exclusion of PZA in the TB treatment regimen could potentially affect the biomarker signature detected in the circulation of TB patients.

Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis

“…Taken together, these effects in the spleen as a result of low dose PAEs or oral PZA demonstrate a systemic effect. Given that such low doses of drug delivered by two routes of administration exhibited these systemic effects, it is possible that they are a consequence of immunomodulatory effects of PZA and PZA analogs (17,18). To our knowledge, this is the first report of low dose oral PZA treatment having any effectiveness and it is potentially relevant to treatment of susceptible TB.…”

“…Further, PZA is the only antitubercular agent known to efficiently diffuse into the caseum of lung granulomas (16). PZA is also reported to modulate host immune responses (17,18). An immunomodulatory effect of PZA might be an additional factor contributing to TB treatment success.…”

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

“…This was highlighted in a recent study, where nutrient-starved M. tuberculosis displayed increased susceptibility to PZA due to the decreased membrane potential (68). Furthermore, PZA treatment of mice infected with M. tuberculosis significantly reduces the release of proinflammatory cytokines and chemokines, suggesting that PZA has important host-directed effects (69). Due to the importance of ATP for cellular viability, the components involved in the process of ATP production represent viable drug targets which, in combination with current anti-TB drugs, could be used for effective treatment.…”

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].…”