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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 canonical PPAR and NF-kB pathway genes in the untreated or PZA-treated infected mouse lungs.(A). Canonical PPAR and NF-kB pathway map showing interaction of genes in the untreated Mtb-infected mouse lungs at 42 days. The legends for gene symbols are the same as in Figure 4. Red and green symbols in the networks indicate up-, and down-regulation of SDEG and the gradation in the color intensity of symbols is proportional to their relative expression level. (B). Intensity map of 41 SDEG involved in the PPAR and NF-kB pathways in the untreated and PZA-treated 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-g005: Expression of canonical PPAR and NF-kB pathway genes in the untreated or PZA-treated infected mouse lungs.(A). Canonical PPAR and NF-kB pathway map showing interaction of genes in the untreated Mtb-infected mouse lungs at 42 days. The legends for gene symbols are the same as in Figure 4. Red and green symbols in the networks indicate up-, and down-regulation of SDEG and the gradation in the color intensity of symbols is proportional to their relative expression level. (B). Intensity map of 41 SDEG involved in the PPAR and NF-kB pathways in the untreated and PZA-treated 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 reduced the pro-inflammatory cytokine levels in human monocytes and down-regulated the expression of many genes involved in inflammatory response network and TLR signaling in mouse lungs, we investigated the possible mechanism for the anti-inflammatory activities of PZA. We interrogated the microarray gene expression data from Mtb-infected and PZA treated or untreated mouse lungs at 42 and 63 days to identify the transcriptional regulators (TR) that are significantly differentially expressed in the PZA exposed group. Using the IPA down-stream analysis algorithm, we have identified pparg (Peroxisome Proliferator-Activated Receptor, Gamma) as the most significantly differentially expressed, among 36 TR with a regulation z-score value greater than 2. The IPA software uses regulation z-score algorithm to derive functional predictions for the gene expression changes in a dataset. This algorithm is designed in such a way to reduce the chance that random data points will generate significant biological function predictions. We analyzed the expression profile of genes in the PPAR canonical pathway using microarray data from Mtb-infected and PZA treated or untreated mouse lungs at 42 and 63 days post-infection (Figure 5). Of the 41 genes in the PPAR pathway, 16 were up-, and 3 were down-regulated in the Mtb-infected relative to uninfected mouse lungs at 42 days. The number of up-regulated SDEG increased to 29 and none of the 41 SDEGs were down-regulated at 63days. In addition, 22 and 12 genes were either not expressed or had insignificant levels at 42 and 63 days, respectively (Figure 5B). Compared to the untreated infected animal, PZA-treatment up-regulated a larger number of SDEG in the mouse lungs at 42 days (19 versus 16), while equal numbers of SDEG were down-regulated and only 3 were either not expressed or had insignificant levels between these two groups. However, at 63days, 10 SDEG were up-, and 12 were down-regulated, and 19 SDEG were either not expressed or had insignificant levels in the PZA-treated infected mice. In summary, while many of the Mtb-induced genes in the PPAR and in the NF-kB pathways were down-regulated by PZA-treatment, a distinct sub-set of genes (pparg, ryr2, adrb3, chrm2 and lcad) were up-regulated in the treated infected animals at both 42 and 63days (Figure 5B).


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 canonical PPAR and NF-kB pathway genes in the untreated or PZA-treated infected mouse lungs.(A). Canonical PPAR and NF-kB pathway map showing interaction of genes in the untreated Mtb-infected mouse lungs at 42 days. The legends for gene symbols are the same as in Figure 4. Red and green symbols in the networks indicate up-, and down-regulation of SDEG and the gradation in the color intensity of symbols is proportional to their relative expression level. (B). Intensity map of 41 SDEG involved in the PPAR and NF-kB pathways in the untreated and PZA-treated 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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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3755974&req=5

pone-0074082-g005: Expression of canonical PPAR and NF-kB pathway genes in the untreated or PZA-treated infected mouse lungs.(A). Canonical PPAR and NF-kB pathway map showing interaction of genes in the untreated Mtb-infected mouse lungs at 42 days. The legends for gene symbols are the same as in Figure 4. Red and green symbols in the networks indicate up-, and down-regulation of SDEG and the gradation in the color intensity of symbols is proportional to their relative expression level. (B). Intensity map of 41 SDEG involved in the PPAR and NF-kB pathways in the untreated and PZA-treated 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 reduced the pro-inflammatory cytokine levels in human monocytes and down-regulated the expression of many genes involved in inflammatory response network and TLR signaling in mouse lungs, we investigated the possible mechanism for the anti-inflammatory activities of PZA. We interrogated the microarray gene expression data from Mtb-infected and PZA treated or untreated mouse lungs at 42 and 63 days to identify the transcriptional regulators (TR) that are significantly differentially expressed in the PZA exposed group. Using the IPA down-stream analysis algorithm, we have identified pparg (Peroxisome Proliferator-Activated Receptor, Gamma) as the most significantly differentially expressed, among 36 TR with a regulation z-score value greater than 2. The IPA software uses regulation z-score algorithm to derive functional predictions for the gene expression changes in a dataset. This algorithm is designed in such a way to reduce the chance that random data points will generate significant biological function predictions. We analyzed the expression profile of genes in the PPAR canonical pathway using microarray data from Mtb-infected and PZA treated or untreated mouse lungs at 42 and 63 days post-infection (Figure 5). Of the 41 genes in the PPAR pathway, 16 were up-, and 3 were down-regulated in the Mtb-infected relative to uninfected mouse lungs at 42 days. The number of up-regulated SDEG increased to 29 and none of the 41 SDEGs were down-regulated at 63days. In addition, 22 and 12 genes were either not expressed or had insignificant levels at 42 and 63 days, respectively (Figure 5B). Compared to the untreated infected animal, PZA-treatment up-regulated a larger number of SDEG in the mouse lungs at 42 days (19 versus 16), while equal numbers of SDEG were down-regulated and only 3 were either not expressed or had insignificant levels between these two groups. However, at 63days, 10 SDEG were up-, and 12 were down-regulated, and 19 SDEG were either not expressed or had insignificant levels in the PZA-treated infected mice. In summary, while many of the Mtb-induced genes in the PPAR and in the NF-kB pathways were down-regulated by PZA-treatment, a distinct sub-set of genes (pparg, ryr2, adrb3, chrm2 and lcad) were up-regulated in the treated infected animals at both 42 and 63days (Figure 5B).

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