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Host targeted activity of pyrazinamide in Mycobacterium tuberculosis infection.

Manca C, Koo MS, Peixoto B, Fallows D, Kaplan G, Subbian S - PLoS ONE (2013)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers The State University of New Jersey, Newark, New Jersey, United States of America.

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.

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Expression of lung inflammatory response network genes in the untreated or PZA-treated mice.(A). Interaction of genes involved in the host inflammatory response network in the untreated Mtb-infected mouse lungs at 42 days. Red and green symbols in the networks indicate up-, and down-regulated SDEG and the gradation in the color intensity of symbols is proportional to their relative expression levels. (B). Intensity map of 28 SDEG in the untreated and PZA-treated Mtb-infected mouse lungs at 42 and 63 days. The scale bar ranges from +3 (up-regulated; red) to –3 (down-regulated; blue).
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pone-0074082-g004: Expression of lung inflammatory response network genes in the untreated or PZA-treated mice.(A). Interaction of genes involved in the host inflammatory response network in the untreated Mtb-infected mouse lungs at 42 days. Red and green symbols in the networks indicate up-, and down-regulated SDEG and the gradation in the color intensity of symbols is proportional to their relative expression levels. (B). Intensity map of 28 SDEG in the untreated and PZA-treated Mtb-infected mouse lungs at 42 and 63 days. The scale bar ranges from +3 (up-regulated; red) to –3 (down-regulated; blue).

Mentions: Since PZA-treatment of Mtb-infected human primary cells and mouse lungs reduced IL-1β, IL-6, TNF-α and MCP-1 at the protein and gene transcription levels, respectively, we hypothesized that PZA-treatment reduce general lung inflammation in Mtb-infected mice. To address the effect of PZA treatment on the lung inflammation, we analyzed the level and pattern of expression of inflammatory response network genes in mouse lungs at 42 and 63 days and compared to the untreated counterpart (Figure 4). A total of 28 SDEG were involved in the inflammatory response network. These genes encode transcriptional regulators (stat1, irf1, spi1 and hif1a), cytokines and chemokines (cxcl10, ccl5 and hk2), enzymes (slfn13, herc6, paics, trim21 and pnp) and membrane receptors (tlr4, cd40, b2m, hlab and ccr2). All of these SDEG at 42 days and 23 out of 28 SDEGs at 63 days were up-regulated in the lungs of untreated infected mice (Figure 4B). In contrast, 20 and 21 out of 28 SDEGs in the inflammatory network genes were significantly down-regulated in the PZA-treated, relative to untreated, infected lungs at 42 and 63 days, respectively. The expression levels of snrpg was similar between untreated and PZA-treated, while 7 and 5 out of 28 SDEGs were either not expressed or had insignificant levels in the PZA-treated mouse lungs at 42 and 63 days, respectively (Figure 4B).


Host targeted activity of pyrazinamide in Mycobacterium tuberculosis infection.

Manca C, Koo MS, Peixoto B, Fallows D, Kaplan G, Subbian S - PLoS ONE (2013)

Expression of lung inflammatory response network genes in the untreated or PZA-treated mice.(A). Interaction of genes involved in the host inflammatory response network in the untreated Mtb-infected mouse lungs at 42 days. Red and green symbols in the networks indicate up-, and down-regulated SDEG and the gradation in the color intensity of symbols is proportional to their relative expression levels. (B). Intensity map of 28 SDEG in the untreated and PZA-treated Mtb-infected mouse lungs at 42 and 63 days. The scale bar ranges from +3 (up-regulated; red) to –3 (down-regulated; blue).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755974&req=5

pone-0074082-g004: Expression of lung inflammatory response network genes in the untreated or PZA-treated mice.(A). Interaction of genes involved in the host inflammatory response network in the untreated Mtb-infected mouse lungs at 42 days. Red and green symbols in the networks indicate up-, and down-regulated SDEG and the gradation in the color intensity of symbols is proportional to their relative expression levels. (B). Intensity map of 28 SDEG in the untreated and PZA-treated Mtb-infected mouse lungs at 42 and 63 days. The scale bar ranges from +3 (up-regulated; red) to –3 (down-regulated; blue).
Mentions: Since PZA-treatment of Mtb-infected human primary cells and mouse lungs reduced IL-1β, IL-6, TNF-α and MCP-1 at the protein and gene transcription levels, respectively, we hypothesized that PZA-treatment reduce general lung inflammation in Mtb-infected mice. To address the effect of PZA treatment on the lung inflammation, we analyzed the level and pattern of expression of inflammatory response network genes in mouse lungs at 42 and 63 days and compared to the untreated counterpart (Figure 4). A total of 28 SDEG were involved in the inflammatory response network. These genes encode transcriptional regulators (stat1, irf1, spi1 and hif1a), cytokines and chemokines (cxcl10, ccl5 and hk2), enzymes (slfn13, herc6, paics, trim21 and pnp) and membrane receptors (tlr4, cd40, b2m, hlab and ccr2). All of these SDEG at 42 days and 23 out of 28 SDEGs at 63 days were up-regulated in the lungs of untreated infected mice (Figure 4B). In contrast, 20 and 21 out of 28 SDEGs in the inflammatory network genes were significantly down-regulated in the PZA-treated, relative to untreated, infected lungs at 42 and 63 days, respectively. The expression levels of snrpg was similar between untreated and PZA-treated, while 7 and 5 out of 28 SDEGs were either not expressed or had insignificant levels in the PZA-treated mouse lungs at 42 and 63 days, respectively (Figure 4B).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers The State University of New Jersey, Newark, New Jersey, United States of America.

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.

Show MeSH
Related in: MedlinePlus