Tag Archives: Helmholtz Zentrum München

Nanoparticles can activate viruses lying dormant in lung cells

The nanoparticles in question are from combustion engines, which means that we are exposed to them. One other note, the testing has not been done on humans but rather on cells. From a Jan. 16, 2017 news item on ScienceDaily,

Nanoparticles from combustion engines can activate viruses that are dormant in in lung tissue cells. This is the result of a study by researchers of Helmholtz Zentrum München, a partner in the German Center for Lung Research (DZL), which has now been published in the journal Particle and Fibre Toxicology.

To evade the immune system, some viruses hide in cells of their host and persist there. In medical terminology, this state is referred to as a latent infection. If the immune system becomes weakened or if certain conditions change, the viruses become active again, begin to proliferate and destroy the host cell. A team of scientists led by Dr. Tobias Stöger of the Institute of Lung Biology and Prof. Dr. Heiko Adler, deputy head of the research unit Lung Repair and Regeneration at Helmholtz Zentrum München, now report that nanoparticles can also trigger this process.

A Jan. 16, 2017 Helmholtz Zentrum München press release (also on EurekAlert), which originated the news item, provides more detail,

“From previous model studies we already knew that the inhalation of nanoparticles has an inflammatory effect and alters the immune system,” said study leader Stöger. Together with his colleagues Heiko Adler and Prof. Dr. Philippe Schmitt-Kopplin, he showed that “an exposure to nanoparticles can reactivate latent herpes viruses in the lung.”

Specifically, the scientists tested the influence of nanoparticles typically generated by fossil fuel combustion in an experimental model for a particular herpes virus infection. They detected a significant increase in viral proteins, which are only produced with active virus proliferation. “Metabolic and gene expression analyses also revealed patterns resembling acute infection,” said Philippe Schmitt-Kopplin, head of the research unit Analytical BioGeoChemistry (BGC). Moreover, further experiments with human cells demonstrated that Epstein-Barr viruses are also ‘awakened’ when they come into contact with the nanoparticles.

Potential approach for chronic lung diseases

In further studies, the research team would like to test whether the results can also be transferred to humans. “Many people carry herpes viruses, and patients with idiopathic pulmonary fibrosis are particularly affected,” said Heiko Adler. “If the results are confirmed in humans, it would be important to investigate the molecular process of the reactivation of latent herpes viruses induced by particle inhalation. Then we could try to influence this pathway therapeutically.”

Special cell culture models shall therefore elucidate the exact mechanism of virus reactivation by nanoparticles. “In addition,” Stöger said, ”in long-term studies we would like to investigate to what extent  repeated nanoparticle exposure with corresponding virus reactivation leads to chronic inflammatory and remodeling processes in the lung.”

Further Information

In 2015 another group at the Helmholtz Zentrum München demonstrated how the Epstein-Barr virus  hides in human cells. In March 2016 researchers also showed that microRNAs silence immune alarm signals of cells infected with the Epstein-Barr virus.

Original Publication:
Sattler, C. et al. (2016): Nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection. Particle and Fibre Toxicology, DOI 10.1186/s12989-016-0181-1

Here’s a link to and a citation for the paper on investigating latent herpes virus,

Nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection by Christine Sattler, Franco Moritz, Shanze Chen, Beatrix Steer, David Kutschke, Martin Irmler, Johannes Beckers, Oliver Eickelberg, Philippe Schmitt-Kopplin, Heiko Adler. Particle and Fibre Toxicology201714:2 DOI: 10.1186/s12989-016-0181-1 Published: 10 January 2017

©  The Author(s). 2017

This paper is open access and, so too, is the 2016 paper.

Lungs: EU SmartNanoTox and Pneumo NP

I have three news bits about lungs one concerning relatively new techniques for testing the impact nanomaterials may have on lungs and two concerning developments at PneumoNP; the first regarding a new technique for getting antibiotics to a lung infected with pneumonia and the second, a new antibiotic.

Predicting nanotoxicity in the lungs

From a June 13, 2016 news item on Nanowerk,

Scientists at the Helmholtz Zentrum München [German Research Centre for Environmental Health] have received more than one million euros in the framework of the European Horizon 2020 Initiative [a major European Commission science funding initiative successor to the Framework Programme 7 initiative]. Dr. Tobias Stöger and Dr. Otmar Schmid from the Institute of Lung Biology and Disease and the Comprehensive Pneumology Center (CPC) will be using the funds to develop new tests to assess risks posed by nanomaterials in the airways. This could contribute to reducing the need for complex toxicity tests.

A June 13, 2016 Helmholtz Zentrum München (German Research Centre for Environmental Health) press release, which originated the news item, expands on the theme,

Nanoparticles are extremely small particles that can penetrate into remote parts of the body. While researchers are investigating various strategies for harvesting the potential of nanoparticles for medical applications, they could also pose inherent health risks*. Currently the hazard assessment of nanomaterials necessitates a complex and laborious procedure. In addition to complete material characterization, controlled exposure studies are needed for each nanomaterial in order to guarantee the toxicological safety.

As a part of the EU SmartNanoTox project, which has now been funded with a total of eight million euros, eleven European research partners, including the Helmholtz Zentrum München, want to develop a new concept for the toxicological assessment of nanomaterials.

Reference database for hazardous substances

Biologist Tobias Stöger and physicist Otmar Schmid, both research group heads at the Institute of Lung Biology and Disease, hope that the use of modern methods will help to advance the assessment procedure. “We hope to make more reliable nanotoxicity predictions by using modern approaches involving systems biology, computer modelling, and appropriate statistical methods,” states Stöger.

The lung experts are concentrating primarily on the respiratory tract. The approach involves defining a representative selection of toxic nanomaterials and conducting an in-depth examination of their structure and the various molecular modes of action that lead to their toxicity. These data are then digitalized and transferred to a reference database for new nanomaterials. Economical tests that are easy to conduct should then make it possible to assess the toxicological potential of these new nanomaterials by comparing the test results s with what is already known from the database. “This should make it possible to predict whether or not a newly developed nanomaterial poses a health risk,” Otmar Schmid says.

* Review: Schmid, O. and Stoeger, T. (2016). Surface area is the biologically most effective dose metric for acute nanoparticle toxicity in the lung. Journal of Aerosol Science, DOI:10.1016/j.jaerosci.2015.12.006

The SmartNanoTox webpage is here on the European Commission’s Cordis website.

Carrying antibiotics into lungs (PneumoNP)

I received this news from the European Commission’s PneumoNP project (I wrote about PneumoNP in a June 26, 2014 posting when it was first announced). This latest development is from a March 21, 2016 email (the original can be found here on the How to pack antibiotics in nanocarriers webpage on the PneumoNP website),

PneumoNP researchers work on a complex task: attach or encapsulate antibiotics with nanocarriers that are stable enough to be included in an aerosol formulation, to pass through respiratory tracts and finally deliver antibiotics on areas of lungs affected by pneumonia infections. The good news is that they finally identify two promising methods to generate nanocarriers.

So far, compacting polymer coils into single-chain nanoparticles in water and mild conditions was an unsolved issue. But in Spain, IK4-CIDETEC scientists developed a covalent-based method that produces nanocarriers with remarkable stability under those particular conditions. Cherry on the cake, the preparation is scalable for more industrial production. IK4-CIDETEC patented the process.

Fig.: A polymer coil (step 1) compacts into a nanocarrier with cross-linkers (step 2). Then, antibiotics get attached to the nanocarrier (step 3).

Fig.: A polymer coil (step 1) compacts into a nanocarrier with cross-linkers (step 2). Then, antibiotics get attached to the nanocarrier (step 3).

At the same time, another route to produce lipidic nanocarriers have been developed by researchers from Utrecht University. In particular, they optimized the method consisting in assembling lipids directly around a drug. As a result, generated lipidic nanocarriers show encouraging stability properties and are able to carry sufficient quantity of antibiotics.

Fig.: On presence of antibiotics, the lipidic layer (step 1) aggregates the the drug (step 2) until the lipids forms a capsule around the antibiotics (step 3).

Fig.: On presence of antibiotics, a lipidic layer (step 1) aggregates the drug (step 2) until the lipids forms a capsule around antibiotics (step 3).

Assays of both polymeric and lipidic nanocarriers are currently performed by ITEM Fraunhofer Institute in Germany, Ingeniatrics Tecnologias in Spain and Erasmus Medical Centre in the Netherlands. Part of these tests allows to make sure that the nanocarriers are not toxic to cells. Other tests are also done to verify that the efficiency of antibiotics on Klebsiella Pneumoniae bacteria when they are attached to nanocarriers.

A new antibiotic for pneumonia (PneumoNP)

A June 14, 2016 PneumoNP press release (received via email) announces work on a promising new approach to an antibiotic for pneumonia,

The antimicrobial peptide M33 may be the long-sought substitute to treat difficult lung infections, like multi-drug resistant pneumonia.

In 2013, the European Respiratory Society predicted 3 millions cases of pneumonia in Europe every year [1]. The standard treatment for pneumonia is an intravenous administration of a combination of drugs. This leads to the development of antibiotic resistance in the population. Gradually, doctors are running out of solutions to cure patients. An Italian company suggests a new option: the M33 peptide.

Few years ago, the Italian company SetLance SRL decided to investigate the M33 peptide. The antimicrobial peptide is an optimized version of an artificial peptide sequence selected for its efficacy and stability. So far, it showed encouraging in-vitro results against multidrug-resistant Gram-negative bacteria, including Klebsiella Pneumoniae. With the support of EU funding to the PneumoNP project, SetLance SRL had the opportunity to develop a new formulation of M33 that enhances its antimicrobial activity.

The new formulation of M33 fights Gram-negative bacteria in three steps. First of all, the M33 binds with the lipopolysaccharides (LPS) on the outer membrane of bacteria. Then, the molecule forms a helix and finally disrupts the membrane provoking cytoplasm leaking. The peptide enabled up to 80% of mices to survive Pseudomonas Aeruginosa-based lung infections. Beyond these encouraging results, toxicity to the new M33 formulation seems to be much lower than antimicrobial peptides currently used in clinical practice like colistin [2].

Lately, SetLance scaled-up the synthesis route and is now able to produce several hundred milligrams per batch. The molecule is robust enough for industrial production. We may expect this drug to go on clinical development and validation at the beginning of 2018.

[1] http://www.erswhitebook.org/chapters/acute-lower-respiratory-infections/pneumonia/
[2] Ceccherini et al., Antimicrobial activity of levofloxacin-M33 peptide conjugation or combination, Chem Med Comm. 2016; Brunetti et al., In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Scientific Reports 2016

I believe all the references are open access.

Brief final comment

The only element linking these news bits together is that they concern the lungs.