Schematic representation of how a C. pneumoniae cell infects a human cell. The bacterium injects the protein SemD (green) into the cell, which activates the cell protein N-WASP, which in turn initiates vesicle formation.
Credit: HHU/Fabienne Kocher.
The problem of parasites for creationists is one that, despite the best efforts of apologists like Michael J Behe of the Deception Institute, just won't go away.
Sadly, Behe shot himself in the foot with his original claim to have proven 'intelligent [sic] design in living organisms with his choice of the bacterial flagellum in E. coli, where he persuaded his willing audience that these nasty little pathogens had been intelligently designed - and by unspoken assumption, designed by the locally-popular god.
Now creationists wave his 'proof' of design as evidence for their creator god because only their god is capable of creating living organisms.
But, with characteristic double-think, creationists also argue that their god is omnibenevolent, so something else must have created parasites like E. coli, and, courtesy again of Michael J. Behe, they cite 'Sin' causing 'genetic entropy' and the absurd idea of 'devolution' this supposedly causes, as the cause of parasites and pathogens (but not the bacterial flagellum, obviously!).
The problem with that notion is that they need to do their double-think trick one more time and believe that a trait with improves a pathogens ability to live and reproduce in its host makes it somehow less perfect that one without that trait. So, in the creationist's world, an improvement is a move away from perfection!
But, with a cult that appears to believe learning is a move away from the 'perfection' of pristine ignorance (from whence comes expertise in all aspects of science), that's probably not too difficult a feat of mental gymnastics for a creationist to perform.
Tell me all about Chlamydia pneumoniae, its evolution and the aetiology of the diseases it causes, please. Chlamydia pneumoniae: Overview and AetiologyWith that in mind, it would be interesting to discover how creationists fit the news that a team of biologists from Heinrich Heine University Düsseldorf (HHU), have worked out how the pathogenic bacterium, Chlamydia pneumoniae attacks human cells and causes the diseases associated with it. These abilities make the bacterium better at doing what they appear to have been 'designed' to do, so any explanation for why they shouldn't be attributed to creationism's intelligent [sic] designer should include a mechanism by which something else can also design and create living organisms.
Chlamydia pneumoniae is a species of bacteria in the Chlamydiaceae family, which is an obligate intracellular pathogen. It primarily causes respiratory infections in humans, including bronchitis, pneumonia, and sinusitis, and has been implicated in more severe diseases like atherosclerosis and possibly Alzheimer's disease.
Aetiology of Diseases The diseases caused by Chlamydia pneumoniae are mainly respiratory in nature, with pneumonia being the most prominent. Here's a breakdown of its role in disease:
- Respiratory Infections
C. pneumoniae typically infects the respiratory tract, causing mild to severe illnesses. Common manifestations include:
- Bronchitis: Inflammation of the bronchi, leading to coughing, mucus production, and difficulty breathing.
- Sinusitis: Inflammation of the sinuses, often presenting with nasal congestion, facial pain, and headaches.
- Pneumonia: C. pneumoniae is known to cause community-acquired pneumonia, which is a lung infection marked by fever, chest pain, and cough. The infection can range from mild to severe and may require hospitalization.
- Atherosclerosis
There is evidence suggesting that C. pneumoniae may contribute to atherosclerosis, a condition characterized by the buildup of plaque in arteries, which can lead to cardiovascular diseases such as heart attacks and strokes. The proposed mechanism involves chronic inflammation triggered by the bacterial infection, which promotes the formation of arterial plaque.- Neurological Diseases
Some studies have suggested a potential link between C. pneumoniae and neurological conditions like Alzheimer's disease. This connection is still under investigation, but one hypothesis is that C. pneumoniae might infect the brain, triggering inflammation and neuronal damage that contribute to cognitive decline.
Pathogenesis
C. pneumoniae follows a biphasic developmental cycle that is characteristic of Chlamydia species:
- Elementary Bodies (EBs): These are the infectious, extracellular form of the bacterium. Once they enter a host cell (usually epithelial cells in the lungs), they transform into the next stage.
- Reticulate Bodies (RBs): These are the non-infectious, intracellular form that divides and multiplies within the host cell. After replication, RBs revert to EBs, which are released when the host cell bursts, allowing the cycle to continue.
The bacteria use specialized mechanisms to evade the host’s immune system and persist within cells, leading to chronic or recurring infections.
Evolution of Chlamydia pneumoniae The evolutionary history of C. pneumoniae is closely tied to other species in the Chlamydia genus, such as Chlamydia trachomatis (which causes sexually transmitted infections) and Chlamydia pneumoniae (responsible for psittacosis, a zoonotic disease). These bacteria share a common ancestor and have adapted to different ecological niches, including human respiratory tracts (C. pneumoniae) and the genital tract (C. trachomatis).
- Intracellular Lifestyle: The obligate intracellular nature of C. pneumoniae evolved as a survival mechanism, allowing the bacterium to escape host immune responses and persist in harsh environments inside cells.
- Host Adaptation: Initially, C. pneumoniae might have been a pathogen of animals before jumping to humans, as many chlamydial species infect animals. Over time, it adapted to the human respiratory system.
- Genetic Conservation and Variation: C. pneumoniae shares highly conserved genomic elements with other chlamydial species, but some genetic differences allow it to infect specific tissues and cause respiratory diseases, whereas other species cause urogenital or zoonotic infections.
Transmission
C. pneumoniae is primarily transmitted through respiratory droplets. Close contact with an infected person, such as coughing or sneezing, facilitates the spread of the bacteria. It can survive in aerosols, making it relatively easy to spread in enclosed or crowded spaces.
Diagnosis and Treatment
- Diagnosis:
- Serology: Detects antibodies against C. pneumoniae.
- Polymerase Chain Reaction (PCR): Identifies bacterial DNA in clinical samples like sputum or nasal swabs.
- Culture: While possible, culturing C. pneumoniae is difficult due to its intracellular nature.
- Treatment:
- C. pneumoniae infections are typically treated with antibiotics such as macrolides (e.g., azithromycin), tetracyclines (e.g., doxycycline), or fluoroquinolones.
- Early detection and treatment are essential to prevent complications like chronic infections or secondary cardiovascular issues.
Public Health Impact
C. pneumoniae infections are common worldwide, with a high prevalence of asymptomatic cases, which makes the pathogen difficult to track. Infections are most common in school-aged children, young adults, and the elderly, particularly in crowded environments. The bacterium has become an important focus of research due to its potential role in chronic diseases like atherosclerosis and Alzheimer’s, which, if confirmed, could make it a major target for therapeutic interventions in the future.
Is Chlamydia pneumoniae specific to humans?
No, Chlamydia pneumoniae is not entirely specific to humans, though humans are its primary host. It has also been detected in animals, including some species of reptiles, koalas, horses, and frogs. However, the strains infecting these animals can differ genetically from those that infect humans. The ability of C. pneumoniae to cross species boundaries is an interesting aspect of its biology, but infections in animals are not as well studied or as common as in humans.
The human-adapted strain of C. pneumoniae primarily causes respiratory infections, while infections in animals tend to be less frequent and not as well documented. It is thought that the bacterium might have originally evolved in animals before jumping to humans and adapting to the human respiratory tract. This zoonotic potential shows that C. pneumoniae is versatile, even though its primary pathogenic role is in human disease.
The HHU team's findings have just been published, open access, in Nature Communications. They are also the subject of an HHU News release:
How Chlamydia manipulate the host cellThe paper in Nature Communications is rather technical, but creationists purporting to be leading experts in the field of microbiology, which many of them pose as, should have no difficulty pointing out which aspects of the parasite were caused by 'genetic entropy' [sic] and what the initial perfection from which these have 'devolved' [sic] would have been.
Bacteria that cause diseases, so-called pathogens, develop various strategies to exploit human cells as hosts to their own advantage. Together with medical professionals and experts for structure determination and imaging, a team of biologists from Heinrich Heine University Düsseldorf (HHU) has uncovered the attack strategies employed by the bacterium Chlamydia pneumoniae (for short: C. pneumoniae). In the scientific journal Nature Communications, they describe which molecular mechanisms the bacterium utilises.
Chlamydia infect human and animal host cells. C. pneumoniae, for example, is transmitted via droplet infection and attacks the respiratory tract, causing bronchitis, asthma or pneumonia. The pathogens are however also linked with secondary conditions such as Alzheimer’s disease, Reiter’s disease, arteriosclerosis and lung cancer.
At HHU, the research group headed by Senior Professor Dr Johannes H. Hegemann at the Institute for Functional Microbial Genomics has examined the infection mechanisms of the bacterium together with the Center for Structural Studies (CSS), the Center for Advanced Imaging (CAi) and the Institute of Biochemistry and Molecular Biology II at the Medical Faculty (research group headed by Professor Dr Reza Ahmadian). For the first time, the researchers describe the structural and functional methods C. pneumoniae uses to penetrate the human cell: It mimics molecular structures of the human cell (so-called “molecular mimicry”) and uses them for its attack.
The bacterium can only reproduce inside a host cell. To achieve this, it needs to induce the transport machinery of the cell to incorporate it into the host – so-called endocytosis. In this process, the cell membrane curves inwards to surround the small pieces of material to be transported into the cell and then buds off inside the cell to form a membrane-enclosed vesicle containing the material.
The critical element in the process is the inner so-called actin cytoskeleton of the cell, which supplies the energy needed for endocytosis. The process is triggered by the human protein Cdc42 binding to a specific activator (N-WASP).
Lead author Fabienne Kocher, biology PhD student and member of the Manchot Graduate School “Molecules of Infection IV”, explains how C. pneumoniae hijacks endocytosis for its own ends:“Once the pathogen has bound to the outside of the human cell, it injects the chlamydial protein ‘SemD’ into its future host. The SemD then binds from the inside to the membrane of the vesicle which forms, activating the actin cytoskeleton so that the plasma membrane fully engulfs the large Chlamydium.
Fabienne Kocher, lead author
Faculty of Mathematics and Natural Sciences
Institute for Functional Microbial Genomics
Heinrich Heine University, Düsseldorf, Germany.
This alters endocytosis to benefit the bacterium, as the process is not normally intended for the transport of such large structures as an entire bacterium.
We wanted to know how the various molecular structures interact with each other and how the Chlamydia have developed to infect human cells as efficiently as possible. The bacterial protein SemD is in fact optimally tailored to N-WASP: The key section where it binds to N-WASP looks exactly like Cdc42 and it binds even better than the normal activator Cdc42.
Professor Johannes H. Hegemann, corresponding author
Faculty of Mathematics and Natural Sciences
Institute for Functional Microbial Genomics
Heinrich Heine University, Düsseldorf, Germany.
Professor Ahmadian from the Medical Faculty adds: “We were also able to show that SemD even displaces Cdc42, which has already bound to N-WASP, so it can then bind itself.” To enable determination of the structure, the researchers cultivated tiny crystals of SemD with N-WASP and then examined the structure. The team headed by Professor Dr Sander Smits at the CSS was responsible for this: “In order to realise these complex measurements, state-of-the-art technical equipment and above all corresponding personnel are needed. This concentration of infrastructural equipment and personnel expertise is not possible in every laboratory. Special centres – like the CSS established by HHU – are needed.”We hope to be able to develop agents in the future, which can prevent this highly specific interaction between the bacterial and human proteins, and thus block infections by C. pneumoniae.
Fabienne Kocher.
Publication:Fabienne Kocher, Violetta Applegate, Jens Reiners, Astrid Port, Dominik Spona, Sebastian Hänsch, Amin Mirzaiebadizi, Mohammad Reza Ahmadian, Sander H. J. Smits, Johannes H. Hegemann & Katja Mölleken.
The Chlamydia pneumoniae effector SemD exploits its host’s endocytic machinery by structural and functional mimicry.
Nature Communications 15: 7294 (2024) DOI: 10.1038/s41467-024-51681-3.
AbstractIt should be simple then for a creationist to explain why this degree of complexity and a clearly evolved strategy for being better at making us sick than would otherwise be the case, shouldn't be attributed to their putative designer god but should be blamed on some other creative entity over which their reputedly omnipotent god has no control.
To enter epithelial cells, the obligate intracellular pathogen Chlamydia pneumoniae secretes early effector proteins, which bind to and modulate the host-cell’s plasma membrane and recruit several pivotal endocytic host proteins. Here, we present the high-resolution structure of an entry-related chlamydial effector protein, SemD. Co-crystallisation of SemD with its host binding partners demonstrates that SemD co-opts the Cdc42 binding site to activate the actin cytoskeleton regulator N-WASP, making active, GTP-bound Cdc42 superfluous. While SemD binds N-WASP much more strongly than Cdc42 does, it does not bind the Cdc42 effector protein FMNL2, indicating effector protein specificity. Furthermore, by identifying flexible and structured domains, we show that SemD can simultaneously interact with the membrane, the endocytic protein SNX9, and N-WASP. Here, we show at the structural level how a single effector protein can hijack central components of the host’s endocytic system for efficient internalization.
Introduction
The obligate intracellular bacterial pathogen Chlamydia pneumoniae (Cpn) causes infections of the upper and lower respiratory tract1,2. A certain proportion of these can result in severe respiratory illnesses, such as pneumonia, asthma and chronic bronchitis, as well as multiple sclerosis, inflammatory arthritis, lung cancer and Alzheimer’s disease2,3,4,5,6.
Cpn’s developmental cycle begins with the adhesion of the infectious elementary body (EB) to the host-cell’s plasma membrane (PM), and its internalisation into a membrane-enclosed “inclusion”. The initial, transient contact between EB and host cell enables chlamydial surface proteins, such as Pmp proteins and LipP, to stably bind and activate host-cell receptors that trigger receptor-mediated internalisation7,8,9. However, engulfment of the EB requires a membrane vesicle that is three to four times larger in diameter than a classical endocytotic vesicle10. Cpn solves this problem by secreting several entry-related, early effector proteins directly into the host cell via its type-III-secretion system (T3SS). These include soluble factors, such as Cpn0572 (the homologue of Chlamydia trachomatis (Ctr) TarP), and proteins that bind to the host’s PM, such as SemC and SemD11,12,13. By hijacking components of the host’s endocytic machinery, early effectors trigger the formation of an intracellular membrane-enclosed vesicle that encompasses the EB14,15,16. The membrane-bound effectors SemC and SemD play a vital role in this process. Each possesses an amphipathic helix (APH) with high affinity for phosphatidylserine (PS), a specific phospholipid found in the inner leaflet of the PM12,13. The binding of SemC to PS induces extensive membrane curvature while SemD (382 aa) recruits and activates central endocytic host proteins12,13.
Downstream of its N-terminal APH, SemD harbours two proline-rich domains (PRD191-100 and PRD2117-122, Fig. 1a), the first of which binds to the SH3 domain of SNX912. During classical endocytosis, SNX9, a BAR domain (bin-amphiphysin-rvs) protein, binds to the PM, induces membrane curvature and promotes vesicle closure17,18,19. Similarly, by recruiting SNX9 via SemD, Cpn amplifies membrane deformation at the site of EB entry and ensures the closure and maturation of the endocytic vesicle.SemD also possesses two centrally located WH2 domains, which are involved in G-actin binding12. Furthermore, the C-terminal 165 residues (aa 218-382) of SemD are required for recruitment of N-WASP, an endocytic host protein that re-organises the actin cytoskeleton by interacting with the actin-branching complex Arp2/312. N-WASP is a ubiquitously expressed member of the WASP family20. Signal reception and transduction of N-WASP are mediated by its basic region (BR), its GTPase-binding domain (GBD) and its verprolin-central-acidic (VCA) domain, respectively. The GBD domain consists of the Cdc42/Rac interactive domain (CRIB) and a C-sub motif (Fig. 2a)21,22. In resting cells, N-WASP resides in an autoinhibited cytosolic state mediated by intramolecular interactions between the GBD and VCA domains22,23. During endocytosis, Cdc42, a small GTPase belonging to the Rho family, is activated by guanine nucleotide exchange factors (GEFs) that catalyse the replacement of bound GDP by GTP24. Active, GTP-bound Cdc42 (Cdc42GTP) binds to the BR-GBD domain of N-WASP, and triggers the release of the VCA domain, which in turn binds and actives the Arp2/3 complex (Supplementary Fig. 2b)23,25. Moreover, the BR binds to PI(4,5)P2 in the inner leaflet of the PM, and recruits the actin polymerisation machinery to the site of endocytosis26.Fig. 1: Crystal structure of SemDΔAPH.
a Schematic representation of the primary structure of SemD, containing an APH49-66, two proline-rich domains (PRD191-100, PRD2117-122) and two WH2 domains (WH2_1138-178, WH2_2179-216). SemDΔAPH67-382 is represented as a black bar. b The structure of SemDΔAPH as resolved by X-ray crystallography. The helices are depicted as cylinders and numbered from 1 to 9, starting at the N-terminus (α1- α9). In accordance with the colour code in a, the WH2_1 and WH2_2 are depicted in orange and red, respectively. The N-terminal E138 and the C-terminal E382 (both marked by black arrows) represent the first and last amino acids visible in the electron density. Right panel: 90° rotation. c SAXS best-fit CORAL model (χ2 value of 1.197), based on the SemDΔAPH crystal structure, and including the added flexible tails (further models are shown in Supplementary Fig. 1h). PRD1 and PRD2 are coloured in green and yellow, respectively. Right panel: 180° rotation. G67 is the N-terminal amino acid, while E382, the last C-terminal residue of SemD, is followed by the C-terminal 10x-His-Tag. d Electrostatic surface representation of SemDΔAPH highlighting the negatively (red) and positively (blue) charged patches. Right panel: 180° rotation.Cdc42 plays a central role in a large number of diverse biological processes such as the cell cycle, controlling gene transcription, regulating the cytoskeleton, cell movement and polarisation, hence being a target for many virulence factors secreted by bacterial pathogens27,28,29. These factors modulate the activity of Cdc42 by mimicking host regulators such as GEFs, GTPase activating proteins (GAPs) and guanine dissociation inhibitors (GDIs), or by covalently modifying Cdc4230,31,32,33,34. In addition, bacterial effector proteins can bind the autoinhibited Cdc42-binding domain of N-WASP, thereby initiating actin polymerisation35. During a Cpn infection, the C-terminus of the membrane-bound SemD interacts with the BR-GBD domain of N-WASP, thus triggering N-WASP activation and Arp2/3-mediated actin polymerisation via an unknown mechanism12. This ensures the provision of branched F-actin bundles required for extensive membrane deformation and maturation of the EB-containing vesicle.Fig. 2: SemD engages with BR-GBD in a Cdc42GTP-mimicking manner.
a Schematic representation of the N-WASP primary sequence. BR-GBD142-273 was used for complex formation with SemDΔAPH. It contains the BR181-197 domain (basic region, cyan), the CRIB198-213 domain (Cdc42/Rac interactive binding motif, magenta) and the C-sub214-250 domain (blue). b The structure of SemDΔAPH in complex with BR-GBD as resolved by X-ray crystallography, shown in cartoon representation. SemDΔAPH is shown in light grey, BR-GBD is coloured in dark grey with the BR domain in cyan, the CRIB domain in magenta and C-sub domain in blue. The zoom in shows details of the binding of SemDΔAPH to BR-GBD. Important residues of SemDΔAPH and BR-GBD are shown in stick representation, while the rest of SemDΔAPH is shown as cartoon. Interactions (<3.5 Å) are shown by the yellow dashes. c Schematic representation of the detailed interactions between SemDΔAPH and BR-GBD. d Electrostatic representation of SemDΔAPH, highlighting the negatively charged patch in red and positively charged surface areas in blue. BR-GBD is coloured in dark grey (cartoon) with the BR domain in cyan and the CRIB domain in magenta, both depicted with stick residues.
In this work, we elucidate the mechanism involved by determining the three-dimensional structure of SemD, alone and in complex with its host interaction partners. We demonstrate that SemD, a protein of 382 aa, can interact simultaneously with the PM, SNX9 and N-WASP, thereby combining membrane association and deformation with modulation of the actin polymerisation machinery. Using small-angle X-ray scattering (SAXS), crystallography and mutational analysis, we show that SemD structurally and functionally mimics the activation of N-WASP by Cdc42GTP, thus enabling Cpn to activate N-WASP in a Cdc42GTP-independent manner. Further, by using pulldown assays and stopped-flow experiments, we show that SemD binds N-WASP more tightly than Cdc42GTP, and that SemD is a specific N-WASP activator, not binding to formin like-protein L2 (FMNL2), another Cdc42GTP-target protein. Our structural data also reveal that the N-WASP binding region of SemD is separated from its PRD1 – which is responsible for SNX9-SH3 binding – and from the membrane-binding APH domain via flexible linker regions. These features permit highly adaptable rearrangements of the individual binding sites, which reduce steric hindrance and facilitate simultaneous binding of the PM, SNX9 and N-WASP. These concurrent interactions enable Cpn to rapidly modulate the PM and the actin cytoskeleton, which ensures the successful formation of a large endocytic vesicle, and the rapid uptake of the EB within 15 minutes after its initial adhesion to a non-phagocytic host cell.
Incidentally, as an added embarrassment for intelligent [sic] design creationists, there is the evidence that this strategy evolved out of the same pre-existing structure (the Type III excretory system) that the E. coli flagellum was known to have evolved from when Behe wrote his book claiming it couldn't have evolved because he couldn't imagine how it could have done.
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
Illustrated by Catherine Webber-Hounslow.
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
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