Lung organoids unveil secret: How pathogens infect human lung tissue
IMAGE:
THE PATHOGENIC BACTERIUM PSEUDOMONAS AERUGINOSA BREACHING THROUGH THE RESPIRATORY EPITHELIA OF A HUMAN LUNG MICROTISSUE MODEL, CAPTURED VIA SCANNING ELECTRON MICROSCOPY.
view moreCREDIT: BENOIT LAVENTIE, BIOZENTRUM, UNIVERSITY OF BASEL
How do pathogens invade the lungs? Using human lung microtissues, a team at the Biozentrum of the University of Basel has uncovered the strategy used by a dangerous pathogen. The bacterium targets specific lung cells and has developed a sophisticated strategy to break through the lungs’ line of defense.
Earlier this year, the WHO published a list of twelve of the world’s most dangerous bacterial pathogens that are resistant to multiple antibiotics and pose a grave threat to human health. This list includes Pseudomonas aeruginosa, a much-feared nosocomial pathogen that causes severe and life-threatening pneumonia. This pathogen is especially threatening to immunocompromised patients and those on mechanical ventilation, with mortality rates up to 50 percent.
The lung barrier is penetrable
Pseudomonas aeruginosa has developed a broad range of strategies to invade the lungs and the body. Researchers led by Prof. Urs Jenal at the Biozentrum, University of Basel, have now gained novel insights into the infection process using lab-grown lung microtissues generated from human stem cells. In the scientific journal “Nature Microbiology”, they describe how Pseudomonas breaches the top layer of lung tissue and invades deeper areas. This study was conducted as part of the National Center of Competence in Research (NCCR) “AntiResist”.
Our lungs are lined by a thin layer of tightly packed cells that protects the deeper layers of lung tissue. The surface is covered with mucus, which traps particles such as microorganisms and is removed from the airways by specialized cells. This layer serves as an effective almost impenetrable barrier against invading pathogens. However, Pseudomonas bacteria have found a way to breach it. But how the pathogen crosses the tissue barrier has remained a mystery until now.
Lung organoids provide new insight into infections in humans
“We have grown human lung microtissues that realistically mimic the infection process inside a patient’s body,” explains Jenal. “These lung models enabled us to uncover the pathogen’s infection strategy. It uses the mucus-producing goblet cells as Trojan horses to invade and cross the barrier tissue. By targeting the goblet cells, which make up only a small part of the lung mucosa, the bacteria can breach the defense line and open the gate.”
With a large arsenal of virulence factors, known as secretion systems, the pathogen specifically attacks and invades the goblet cells, replicates inside the cells and ultimately kills them. The burst of the dead cells leads to ruptures in the tissue layer, making the protective barrier leaky. The pathogens exploit this weak spot: They rapidly colonize the rupture sites and spread into deeper tissue regions.
New sensor for monitoring bacteria
Using human lung organoids, the scientists have been able to elucidate the sophisticated infection strategies of Pseudomonas. However, it remains unclear how the pathogens adapt their behavior during the infection process. For example, they must first be mobile to spread over the tissue surface, then quickly adhere to lung cells upon contact, and later activate their virulence factors. It is known that the bacteria can rapidly change their behavior thanks to small signaling molecules. Until now, however, the technology to study these correlations was not available.
Jenal’s team has now developed a biosensor to measure and track a small signaling molecule called c-di-GMP in individual bacteria. The method was recently described in Nature Communications. "This is a technological breakthrough," says Jenal. "Now we can monitor in real time and with high resolution how this signaling molecule is regulated during infection and how it controls the pathogen’s virulence. We now have a detailed view on when and where individual bacterial cells activate certain programs to regulate their behavior. This method enables us to investigate lung infections in more detail."
Organ models mimic conditions in patients
"Thanks to the development of human lung organoids, we now have a much better understanding of how the pathogens behave in human tissue and presumably in patients," emphasizes Jenal. "This brings us a big step closer to the goal of NCCR AntiResist." Organoids of the human lung and other organs like the bladder allow the researchers to study the effects of antibiotics in tissue, for example, identifying where and how bacteria survive during treatment. Such organ models will be indispensable in the future for developing new and effective strategies to combat pathogens.
JOURNAL
Nature Microbiology
ARTICLE TITLE
Goblet cell invasion promotes breaching of respiratory epithelia by an opportunistic human pathogen.
ARTICLE PUBLICATION DATE
10-Jun-2024
Lung cancer screening prolongs lives in real-world study
Among US veterans, screening led to earlier lung cancer diagnoses and improved survival.
Among US veterans diagnosed with lung cancer through the Veterans Health Administration healthcare system, those who underwent screening before diagnosis were more likely to be diagnosed with earlier stage disease and had a higher cure rate than those who had not been screened. The findings come from an observational study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
Lung cancer is the leading cause of cancer deaths worldwide, and most patients are diagnosed at an advanced stage. Early detection through screening could save lives, and current recommendations state that adults 50–80 years old with at least a 20-pack-year smoking history who currently smoke or have quit within the past 15 years should undergo annual imaging tests for lung cancer.
Such screening has been shown to be beneficial in clinical trials, but there are limited data on the real-world effectiveness of lung cancer screening. To investigate, researchers assessed the impact of screening among patients in the Veterans Health Administration healthcare system diagnosed with lung cancer from 2011–2018.
Among 57,919 individuals diagnosed with lung cancer, 2,167 (3.9%) underwent screening before diagnosis. Patients who underwent screening had higher rates of early (stage I) diagnoses compared with those who had no screening (52% versus 27%), lower rates of death from any cause (49.8% versus 72.1%), and death from cancer (41.0% versus 70.3%) over 5 years.
“It is incredible to witness how dedicated national efforts to increase lung cancer screening from the Lung Precision Oncology Program can lead to substantial improvements in lung cancer outcomes,” said co–corresponding author Michael Green, MD, PhD, of the University of Michigan and the Veterans Affairs Ann Arbor Healthcare System.
Additional information
NOTE: The information contained in this release is protected by copyright. Please include journal attribution in all coverage. A free abstract of this article will be available via the CANCER Newsroom upon online publication. For more information or to obtain a PDF of any study, please contact: Sara Henning-Stout, newsroom@wiley.com
Full Citation:
“Impact of Lung Cancer Screening on Stage Migration and Mortality among the National VA Lung Cancer Population.” Donna M. Edwards, Mina Pirzadeh, Tony Van, Ralph Jiang, Akshay Tate, Grace Schaefer, Jadyn James, Caroline Bishop, Cydnee Wilson, Nicholas Nedzesky, Aaren Alseri, Anthony Leveque, Amanda Malus, Akbar Waljee, David A. Elliott, Jane Deng, Ann Schwartz, Matthew Schipper, Alex K. Bryant, Nithya Ramnath, and Michael D. Green. CANCER; Published Online: June 10, 2024 (DOI: 10.1002/cncr.35340).
URL Upon Publication: http://doi.wiley.com/10.1002/cncr.35340
Author Contact: Chris Arbino, Deputy Director of Communications at the VA Ann Arbor Healthcare System, at christopher.arbino@va.gov or +1 734-496-4509
About the Journal
CANCER is a peer-reviewed publication of the American Cancer Society integrating scientific information from worldwide sources for all oncologic specialties. The objective of CANCER is to provide an interdisciplinary forum for the exchange of information among oncologic disciplines concerned with the etiology, course, and treatment of human cancer. CANCER is published on behalf of the American Cancer Society by Wiley and can be accessed online. Follow CANCER on Twitter @JournalCancer and Instagram @ACSJournalCancer, and stay up to date with the American Cancer Society Journals on LinkedIn.
About Wiley
Wiley is a knowledge company and a global leader in research, publishing, and knowledge solutions. Dedicated to the creation and application of knowledge, Wiley serves the world’s researchers, learners, innovators, and leaders, helping them achieve their goals and solve the world's most important challenges. For more than two centuries, Wiley has been delivering on its timeless mission to unlock human potential. Visit us at Wiley.com. Follow us on Facebook, Twitter, LinkedIn and Instagram.
JOURNAL
Cancer
ARTICLE TITLE
Impact of Lung Cancer Screening on Stage Migration and Mortality among the National VA Lung Cancer Population
ARTICLE PUBLICATION DATE
10-Jun-2024
No comments:
Post a Comment