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Autophagy Enhances Bacterial Clearance during P. aeruginosa Lung Infection.

PLoS One. 2013;8(8):e72263

Authors: Junkins RD, Shen A, Rosen K, McCormick C, Lin TJ

Abstract
Pseudomonas aeruginosa is an opportunistic bacterial pathogen which is the leading cause of morbidity and mortality among cystic fibrosis patients. Although P. aeruginosa is primarily considered an extacellular pathogen, recent reports have demonstrated that throughout the course of infection the bacterium acquires the ability to enter and reside within host cells. Normally intracellular pathogens are cleared through a process called autophagy which sequesters and degrades portions of the cytosol, including invading bacteria. However the role of autophagy in host defense against P. aeruginosa in vivo remains unknown. Understanding the role of autophagy during P. aeruginosa infection is of particular importance as mutations leading to cystic fibrosis have recently been shown to cause a blockade in the autophagy pathway, which could increase susceptibility to infection. Here we demonstrate that P. aeruginosa induces autophagy in mast cells, which have been recognized as sentinels in the host defense against bacterial infection. We further demonstrate that inhibition of autophagy through pharmacological means or protein knockdown inhibits clearance of intracellular P. aeruginosa in vitro, while pharmacologic induction of autophagy significantly increased bacterial clearance. Finally we find that pharmacological manipulation of autophagy in vivo effectively regulates bacterial clearance of P. aeruginosa from the lung. Together our results demonstrate that autophagy is required for an effective immune response against P. aeruginosa infection in vivo, and suggest that pharmacological interventions targeting the autophagy pathway could have considerable therapeutic potential in the treatment of P. aeruginosa lung infection.

PMID: 24015228 [PubMed - in process]

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Host Targeted Activity of Pyrazinamide in Mycobacterium tuberculosis Infection.

PLoS One. 2013;8(8):e74082

Authors: Manca C, Koo MS, Peixoto B, Fallows D, Kaplan G, Subbian S

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.

PMID: 24015316 [PubMed - in process]

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection Mediated by the Transmembrane Serine Protease TMPRSS2.

J Virol. 2013 Sep 11;

Authors: Shirato K, Kawase M, Matsuyama S

Abstract
The Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes host proteases for virus entry into lung cells. In the current study, Vero cells constitutively expressing type II transmembrane serine protease (Vero-TMPRSS2 cells) showed larger syncytia at 18 h after infection with MERS-CoV than with other coronaviruses. Furthermore, the susceptibility of Vero-TMPRSS2 cells to MERS-CoV was 100-fold higher than that of non-TMPRSS2-expressing parental Vero cells. The serine protease inhibitor camostat, which inhibits TMPRSS2 activity, completely blocked syncytium formation, but only partially blocked virus entry into Vero-TMPRSS2 cells. Importantly, the coronavirus is thought to enter cells via two distinct pathways, one mediated by TMPRSS2 at the cell surface, and the other mediated by cathepsin L in the endosome. Simultaneous treatment with inhibitors of cathepsin L and TMPRSS2 completely blocked virus entry into Vero-TMPRSS2 cells, indicating that MERS-CoV employs both the cell surface and the endosomal pathway to infect Vero-TMPRSS2 cells. By contrast, a single camostat treatment suppressed MERS-CoV entry into human bronchial submucosal gland-derived Calu-3 cells by 10-fold and virus growth by 270-fold, although treatment with both camostat and EST, a cathepsin inhibitor, or treatment with leupeptin, an inhibitor of cysteine, serine, and threonine peptidases, was no more efficacious than camostat alone. Further, these inhibitors were not efficacious against MERS-CoV infection of MRC-5 and WI-38 cells which derived from lung but these characters differ from mature pneumocytes. These results suggest that a single treatment with camostat is sufficient to block MERS-CoV entry into a well-differentiated lung-derived cell line.

PMID: 24027332 [PubMed - as supplied by publisher]

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Comparison of Mycoplasma pneumoniae Infections in Asthmatic Children Versus Asthmatic Adults.

Pediatr Infect Dis J. 2013 Sep 11;

Authors: Bébéar C, Raherison C, Nacka F, de Barbeyrac B, Pereyre S, Renaudin H, Girodet PO, Marquant F, Desjardins S, Chêne G, Fayon M

Abstract
BACKGROUND:: Mycoplasma pneumoniae has been implicated in asthma exacerbations and chronic asthma. A two-year longitudinal study has been conducted to investigate the role of M. pneumoniae infections in 168 and 20 hospitalized children and adults, respectively, with asthma exacerbation compared with outpatients (88 children and 48 adults) with chronic asthma (without an exacerbation). The prevalence of Chlamydia pneumoniae and respiratory viruses was also assessed in these two populations.
METHODS:: Lung function testing, blood sampling and microbiological testing (PCR, culture and serology) were performed for 256 children and 68 adults followed by a 7-week follow-up visit with repeated blood sampling for serological testing and phone interviews at 6 and 12 months later.
RESULTS:: M. pneumoniae infection was more prevalent in children with chronic asthma (13.6 %) compared with children with exacerbation (7.1 %), while the reverse was true in adults (6.3 vs. 10.0 %, respectively). However, these differences were not statistically significant. Acute C. pneumoniae infection was identified in 3.9% of children and 7.4% adults. Children seen for chronic asthma were significantly more likely to be infected with C. pneumoniae than children hospitalized for an asthma exacerbation. Viruses were the most prevalent microorganisms detected in children with an asthma exacerbation. No differences in the outcome parameters were identified between M. pneumoniae-infected and non-infected patients.
CONCLUSIONS:: The present study suggests that M. pneumoniae does not play a direct role in the pathogenicity of acute or chronic asthma in most children.

PMID: 24030350 [PubMed - as supplied by publisher]