Malevolent Designer - How A Dangerous Pathogen Is Designed to Infect Our Lungs

Pseudomonas aeruginosa

The pathogenic bacterium Pseudomonas aeruginosa breaching through the respiratory epithelia of a human lung microtissue model, captured via Scanning Electron Microscopy.

Image: Benoit Laventie, Biozentrum, University of Basel.

Lung organoids unveil secret: How pathogens infect human lung tissue | University of Basel

A team at the Biozentrum of the University of Basel have shown how a dangerous pathogen gains access to tissues in the lungs, the better to infect them.

To an intelligent [sic] design creationist, there can only be one explanation for this - intelligent design.

To quickly dispense with the traditional excuse offered for this evidence of malevolence, if you subscribe to the intelligent design nonsense - to blame 'Sin' which was caused by 'The Fall', oblivious of the fact that this exposes the intelligent design argument as fundamentalist religion in disguise. Even given a spurious gloss of sciencey-sounding gibberish by Michael J Behe, with his 'genetic entropy' and 'scientifically nonsensical 'devolution' from some assumed created perfection, makes no sense and fails abysmally to rescue creationism from its obvious religious fundamentalism.

No mutation which conveys an advantage, and so progresses to fixation in the species gene pool, can possibly be regarded as 'devolutionary' or less perfect than what went before it, and of course, postulating some assumed initial created perfection simply underlines the religious fundamentalist and the intellectual contortions needed to try to shoehorn the facts into the superstition inherent in the notion.

So, we are left with malevolent intent as the only conclusion, if we subscribe to the intelligent design notion.

Tell me all about Pseudomonas aeruginosa, please. Pseudomonas aeruginosa is a versatile and opportunistic bacterium that can cause a range of infections, especially in individuals with compromised immune systems. Here's a comprehensive overview:

Classification and Characteristics

• Domain: Bacteria
• Phylum: Proteobacteria
• Class: Gammaproteobacteria
• Order: Pseudomonadales
• Family: Pseudomonadaceae
• Genus: Pseudomonas
• Species: Pseudomonas aeruginosa

Morphology

• Shape: Rod-shaped
• Size: Approximately 0.5-0.8 μm in diameter and 1.5-3.0 μm in length
• Motility: Motile due to a single polar flagellum
• Gram Stain: Gram-negative

Metabolism and Growth

• Aerobic: P. aeruginosa is an obligate aerobe, meaning it requires oxygen to grow, but it can also grow in low-oxygen environments through nitrate respiration.
• Metabolic Diversity: It can utilize a variety of organic compounds for growth, contributing to its ability to thrive in diverse environments.
• Temperature: Optimal growth occurs at 37°C (human body temperature), but it can grow at temperatures ranging from 4°C to 42°C.

Habitat

• Natural Reservoirs: Soil, water, and vegetation.
• Nosocomial Presence: Commonly found in hospital environments, where it can contaminate medical equipment and surfaces.

Pathogenicity

• Opportunistic Pathogen: P. aeruginosa primarily infects individuals with weakened immune systems, such as those with cystic fibrosis, burns, or chronic wounds.
• Virulence Factors:
  • Exotoxins: Exotoxin A, which inhibits protein synthesis in host cells.
  • Enzymes: Elastase and alkaline protease, which degrade host tissues and aid in spreading infection.
  • Pigments: Pyocyanin, which produces a characteristic blue-green color and generates reactive oxygen species that damage host tissues.
  • Biofilm Formation: P. aeruginosa can form biofilms, which are protective layers that enhance its resistance to antibiotics and immune responses.
  • Quorum Sensing: A cell-to-cell communication mechanism that regulates virulence gene expression.

Clinical Manifestations

• Respiratory Infections: Particularly severe in cystic fibrosis patients, leading to chronic lung infections.
• Urinary Tract Infections: Especially in catheterized patients.
• Wound Infections: Common in burn victims.
• Bloodstream Infections: Can lead to sepsis, particularly in immunocompromised patients.
• Ear Infections: Including swimmer’s ear (otitis externa).

Antibiotic Resistance

P. aeruginosa is known for its resistance to multiple antibiotics, which is attributed to several mechanisms:

• Efflux Pumps: Proteins that expel antibiotics out of the bacterial cell.
• Beta-lactamases: Enzymes that break down beta-lactam antibiotics.
• Altered Porins: Changes in the bacterial cell wall that reduce antibiotic uptake.
• Biofilm Formation: Protects bacterial communities from antibiotics.

Treatment

• Antibiotic Therapy: Requires combination therapy due to high resistance. Common antibiotics used include aminoglycosides, cephalosporins, carbapenems, and polymyxins.
• Phage Therapy: The use of bacteriophages (viruses that infect bacteria) is being explored as a treatment option.
• Antimicrobial Stewardship: Strategies to minimize resistance development, such as appropriate antibiotic use and infection control measures in healthcare settings.

Prevention and Control

• Hygiene Measures: Regular handwashing and disinfection in hospitals.
• Infection Control Protocols: Isolating infected patients and using personal protective equipment.
• Surveillance: Monitoring for outbreaks and resistance patterns.

Research and Future Directions

• Vaccine Development: Efforts are ongoing to develop vaccines against P. aeruginosa.
• New Antibiotics: Research into novel antimicrobial agents and alternative therapies.
• Understanding Pathogenesis: Studying the genetic and molecular basis of its virulence and resistance mechanisms.

Pseudomonas aeruginosa remains a significant challenge in both clinical and environmental contexts due to its adaptability, resistance, and pathogenic potential. Continued research and vigilant infection control practices are essential to manage and mitigate its impact.

The pathogen in question is Pseudomonas aeruginosa, a dangerous pathogen that causes a severe and life-threatening pneumonia. Not content with giving it the ability to resist antibiotics, the 'designer' has given it additional abilities to ensure it makes us as sick as possible. This enables it to bypass the protective layer the same designer allegedly gave us to protect us from these sorts of parasites - a defence it now apparently regards as a problem to be overcome so its bacterial parasite can do what it was designed to do - give us life-threatening pneumonia.

How it gains entry to the deeper cells in our lungs was discovered by a team of microbiologists from Biozentrum, a research department of the University of Basel, Switzerland, who have written two papers on their findings.

The bacteria first invade the cells in the longs that secrete mucus, known as goblet cells, where they quickly replicate and kill the cell. As the cell bursts it damages the protective top layer of cells, so the bacteria can bypass this layer of protection. The key to its success is its ability to change strategy in response to signal molecules such as c-di-GMP.

This is explained in a news release from the 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. 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.

Professor Urs Jenal, Corresponding author of the first paper, co-corresponding author of the second
Biozentrum
University of Basel, Basel, Switzerland

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. 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.

Professor Urs Jenal.

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. This brings us a big step closer to the goal of NCCR AntiResist.

Professor Urs Jenal.

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.

Original publications

A. Leoni Swart, Benoît-Joseph Laventie, Rosmarie Sütterlin, Tina Junne, Luisa Lauer, Pablo Manfredi, Sandro Jakonia, Xiao Yu, Evdoxia Karagkiozi, Rusudan Okujava and Urs Jenal.
Goblet cell invasion promotes breaching of respiratory epithelia by an opportunistic human pathogen.
Nature Microbiology (2024), doi: 10.1038/s41564-024-01718-6

Andreas Kaczmarczyk, Simon van Vliet, Roman Peter Jakob, Raphael Dias Teixeira, Inga Scheidat, Alberto Reinders, Alexander Klotz, Timm Maier, Urs Jenal.
A genetically-encoded biosensor to monitor dynamic changes of c-di-GMP with high temporal resolution.
Nature Communications (2024), doi: 10.1038/s41467-024-48295-0

The first paper is behind a paywall, so only the abstract is freely available:

Abstract

Pseudomonas aeruginosa, a leading cause of severe hospital-acquired pneumonia, causes infections with up to 50% mortality rates in mechanically ventilated patients. Despite some knowledge of virulence factors involved, it remains unclear how P. aeruginosa disseminates on mucosal surfaces and invades the tissue barrier. Using infection of human respiratory epithelium organoids, here we observed that P. aeruginosa colonization of apical surfaces is promoted by cyclic di-GMP-dependent asymmetric division. Infection with mutant strains revealed that Type 6 Secretion System activities promote preferential invasion of goblet cells. Type 3 Secretion System activity by intracellular bacteria induced goblet cell death and expulsion, leading to epithelial rupture which increased bacterial translocation and dissemination to the basolateral epithelium. These findings show that under physiological conditions, P. aeruginosa uses coordinated activity of a specific combination of virulence factors and behaviours to invade goblet cells and breach the epithelial barrier from within, revealing mechanistic insight into lung infection dynamics.

A. Leoni Swart, Benoît-Joseph Laventie, Rosmarie Sütterlin, Tina Junne, Luisa Lauer, Pablo Manfredi, Sandro Jakonia, Xiao Yu, Evdoxia Karagkiozi, Rusudan Okujava and Urs Jenal.
Goblet cell invasion promotes breaching of respiratory epithelia by an opportunistic human pathogen.
Nature Microbiology (2024), doi: 10.1038/s41564-024-01718-6

© 2024 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

The second (open access) paper discusses the development and use of a specially developed biocensor for detecting changes in c-di-GMP:

Abstract

Monitoring changes of signaling molecules and metabolites with high temporal resolution is key to understanding dynamic biological systems. Here, we use directed evolution to develop a genetically encoded ratiometric biosensor for c-di-GMP, a ubiquitous bacterial second messenger regulating important biological processes like motility, surface attachment, virulence and persistence. The resulting biosensor, cdGreen2, faithfully tracks c-di-GMP in single cells and with high temporal resolution over extended imaging times, making it possible to resolve regulatory networks driving bimodal developmental programs in different bacterial model organisms. We further adopt cdGreen2 as a simple tool for in vitro studies, facilitating high-throughput screens for compounds interfering with c-di-GMP signaling and biofilm formation. The sensitivity and versatility of cdGreen2 could help reveal c-di-GMP dynamics in a broad range of microorganisms with high temporal resolution. Its design principles could also serve as a blueprint for the development of similar, orthogonal biosensors for other signaling molecules, metabolites and antibiotics.

Introduction

The ubiquitous second messenger c-di-GMP plays pivotal roles in many bacteria, regulating behavioral and physiological processes like motility and virulence, or adherence to and growth on surfaces^{1,2,3,4,5,6,7,8}. Accurate control of c-di-GMP was shown to be critical for the establishment of infections and the development of resilience against host-mediated stress and antibiotic therapy in several human pathogens⁹. In most bacteria, regulatory networks controlling c-di-GMP are complex with a multitude of enzymes being responsible for the controlled synthesis and degradation of the signaling compound^10,11,12. For example, the human pathogen Pseudomonas aeruginosa encodes 38 enzymes involved in the “make and break” of c-di-GMP¹³, and in some phyla enzymes regulating c-di-GMP constitute >1% of the organism’s total protein repertoire1. This makes the genetic dissection of the respective regulatory pathways and mechanisms challenging. Much of the information on c-di-GMP control and its role in bacterial physiology and behavior stems from extrapolations of genetic data, generally complemented with invasive biochemical assays providing snapshots of c-di-GMP at steady-state levels and in bulk populations. Because such measurements do not provide single cell information, they fail to visualize signaling heterogeneity in bacterial populations, track dynamic fluctuations in asynchronous populations, or distinguish distinct c-di-GMP-mediated cell fates in bacterial communities. Advancing the mechanistic understanding of c-di-GMP signaling in bacteria thus requires genetically encoded biosensors that monitor dynamic changes of c-di-GMP levels in real-time and in individual cells in a non-invasive manner.

The strong interest in robust biosensors for c-di-GMP or other small molecules has inspired repeated attempts to develop such tools. However, available biosensors generally suffer from major drawbacks. Transcription- or translation-based reporters, although readily available, are generally not suitable for real-time measurements due to considerable temporal delays caused by expression, folding, maturation or stability of the reporters^{14,15,16,17,18,19}. This limitation can be overcome by allosteric sensors operating at the posttranslational level. For instance, a recently described sensor based on bimolecular fluorescence complementation (BiFC) is suitable to measure steady-state levels of c-di-GMP²⁰. However, the irreversible nature of reconstituting a functional fluorescent protein by BiFC²¹ precludes this tool from accurately measuring dynamic c-di-GMP fluctuations. More suitable biosensors that can potentially track changes in c-di-GMP levels in real time make use of Förster resonance energy transfer (FRET) between two fluorescent proteins^22,23,24, or bioluminescence resonance energy transfer (BRET) where a ligand-binding protein is linked to a luciferase and a fluorescent protein²⁵. While FRET sensors can identify and monitor individual cells with different levels of c-di-GMP, they generally lack robustness and, so far, have not been shown to record dynamic changes of c-di-GMP over physiologically relevant time scales. In addition, FRET sensors generally suffer from a limited dynamic range, making them highly susceptible to noise and imposing challenging downstream analysis procedures.

Here we set out to develop a biosensor that overcomes the above limitations and allows monitoring of c-di-GMP dynamics in a diverse range of bacteria by accessing several single-cell techniques, including live-cell microscopy and flow cytometry. Starting from a circularly permuted enhanced green fluorescent protein (cpEGFP) scaffold sandwiched by c-di-GMP-binding domains, we apply a directed evolution-inspired approach^26,27, where c-di-GMP-responsive biosensors with increasing dynamic range and rapid binding kinetics are gradually selected by using iterative fluorescence-activated cell sorting (FACS) under alternating c-di-GMP regimes. The resulting single fluorescent protein biosensor (SFPB), termed cdGreen2, is benchmarked by dissecting the c-di-GMP regulatory networks of two model organisms, the environmental bacterium Caulobacter crescentus and the human pathogen Pseudomonas aeruginosa. The bimodal developmental program of C. crescentus generates a motile and planktonic swarmer (SW) cell and a sessile, surface-attached stalked (ST) cell. Cell differentiation was proposed to depend on precise and genetically hardwired oscillations of c-di-GMP that coordinate cell cycle progression with morphogenesis and behavior^3,19. Similarly, P. aeruginosa undergoes a surface-induced asymmetric program generating motile and sessile offspring to maximize surface colonization^4,28. Similar to C. crescentus, this program was postulated to be orchestrated by the asymmetric distribution of c-di-GMP during the initial cell divisions of surface-adherent P. aeruginosa cells. Using cdGreen2 to visualize c-di-GMP in individual cells, we corroborate these models and define the molecular mechanisms underlying the bimodal phenotypic specialization. We anticipate that cdGreen2 will become a standard molecular tool for the scientific community to dissect the function and mechanisms of c-di-GMP in a large variety of bacteria.

Kaczmarczyk, A., van Vliet, S., Jakob, R.P. et al. A genetically encoded biosensor to monitor dynamic changes of c-di-GMP with high temporal resolution. Nat Commun 15, 3920 (2024). https://doi.org/10.1038/s41467-024-48295-0

Copyright: © 2024 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

The evolutionary explanation for this is perfectly straightforward for anyone who understands even the basics of biological evolution. It's the result of an arms race between a parasite and its host, as it this particular parasite's antibiotic resistance and its colonisation of hospitals where it has become a dangerous nosocomial pathogen with a steady supply of sick people to exploit.

None of this can be excplained in terms of the design of a super0intelligent, omniscient, omnibenevolent designer, however, unless that designer is a pestilential malevolence, forever designing better ways for its parasites to bypass our defenses and increase the suffering in the world.

---

Advertisement

The Unintelligent Designer: Refuting The Intelligent Design Hoax

ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.

Available in Hardcover, Paperback or ebook for Kindle

Advertisement

The Malevolent Designer: Why Nature's God is Not Good

This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.

Illustrated by Catherine Webber-Hounslow.

Available in Hardcover, Paperback or ebook for Kindle

Advertisement

Thank you for sharing!

Tweet Link