Saturday, 10 April 2021

Malevolent Designer News - The Ingenious Way Tuberculosis Poisons You

This transport system may be widespread across many Gram-positive bacteria that contain proteins in the WXG100 superfamily. Tuberculosis kills 1 million people each year.
The tuberculosis pathogen releases its toxin by a novel protein transport system - News | UAB

Creationist mode:


The sheer genius of Creationism's putative Intelligent designer is breath-taking on occasion.

In this case, almost literally, since it concerns the mechanism by which Mycobacterium tuberculosis, the cause of the common lung disease, tuberculosis, kills you. In its determination to make people sick, the Intelligent Designer constantly comes up with these ingenious ways to make sure its nasty little parasites do the job they were designed to do, despite our immune system it allegedly designed to protect us from the organisms it designed to make us suffer.

Scientists at the University of Alabama at Birmingham, Alabama, USA have just published the results of their research in which they discovered that M. tuberculosis not only produces a toxin to poison us with, but it also has a nifty way to make sure we get a good dose of it.

The problem the bacterium has is getting the toxin through its own cell membrane and into the host. Its cell membrane is designed to keep substances inside the cell, not leaking out, so it has to be able to control what leaves and provide it with a means of passing through small, special channels designed for the purpose. It does this by making two small proteins which join together to form dimers. Five of these dimers then join together as a ring in the bacterium's cell membranes to make tiny, star-shaped pores through which the toxins can pass.

Jeff Hansen, in the University of Alabama at Birmingham (UAB) news letter gives the details:
Six years ago, Michael Niederweis, Ph.D., described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis. This toxin, tuberculosis necrotizing toxin, or TNT, became the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. The toxin is released as M. tuberculosis bacteria survive and grow inside their human macrophage host, killing the macrophage and allowing the escape and spread of the bacteria.

Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion. Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria.

EsxE and EsxF constitute the first known outer membrane components mediating protein secretion in M. tuberculosis, however, it is unlikely that EsxE and EsxF are sufficient for TNT secretion, since an energy source is required in all known bacterial protein secretion systems. Therefore, it is possible that EsxE-EsxF associate with other proteins or protein complexes to achieve CpnT export and TNT secretion.

This work was a remarkable achievement of an outstanding graduate student, Uday Tak, who did almost all of these experiments by himself.

Professor Michael Niederweis, Co-author
Department of Microbiology
University of Alabama at Birmingham, AL, USA
For 132 years, the lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death. M. tuberculosis infects 9 million people a year and kills more than 1 million.

Now, in another groundbreaking work, the University of Alabama at Birmingham researcher and colleagues describe how two small ESX proteins made by the M. tuberculosis bacteria mediate secretion of TNT by pore formation in the membranes that envelop the bacteria. This finding may have broad application because a distinctive three-amino acid motif found on EsxE and EsxF — tryptophan/any-amino-acid/glycine, known in shorthand as WXG — is also found on many other small mycobacterium proteins and on the large WXG100 superfamily of bacterial proteins that resemble EsxE and EsxF.

“Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion,” said Niederweis, a professor in the UAB Department of Microbiology. “Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria.”

TNT is one of two domains in the M. tuberculosis outer membrane protein CpnT; activity of the TNT domain of CpnT in the cytosol of the macrophage induces macrophage death by hydrolyzing NAD+. M. tuberculosis has an inner membrane and an outer membrane, and a protein needs to get through each layer to be secreted outside of the bacterium. How CpnT gets to the outer membrane was unknown.

EsxE and EsxF are part of the same gene segment as CpnT, and the UAB researchers hypothesized that the two small proteins might be involved in secretion of the toxin.

By creating different strains that lacked either EsxE or EsxF, they showed that both proteins were necessary for the translocation of CpnT to the cell surface of M. tuberculosis and for the secretion of TNT into the cytosol of macrophages infected with M. tuberculosis. Furthermore, EsxE and EsxF are surface-accessible proteins on M. tuberculosis as a membrane-associated complex.

To learn more about the mechanism of that translocation, the UAB team made mutants of each Esx protein, where the tryptophan amino acid of the single WXG motif on each protein was replaced by the amino acid alanine. The mutants showed that an intact WXG motif on EsxE and on EsxF were required for efficient CpnT translocation to the outer membrane of M. tuberculosis and subsequent TNT secretion into the cytosol of infected macrophages.

Purification of the water-soluble EsxE and EsxF proteins showed they formed EsxE-EsxF dimers, and five of these dimers assembled into star-shaped structures, as viewed by electron microscopy. Each was about 10 nanometers across, with a 3-nanometer central pore.

Experiments with planar lipid bilayers were key to understanding the molecular function of EsxE-EsxF, as they showed that the EsxE-EsxF pores formed channels through lipid membranes.

Finally, the researchers showed that the WXG motifs were required for pore formation and membrane disruption by the EsxE-EsxF complex, and the motifs mediated assembly of functional EsxE-EsxF oligomers. This now defines a biochemical role for the previously enigmatic WXG motif.

“EsxE and EsxF constitute the first known outer membrane components mediating protein secretion in M. tuberculosis,” Niederweis said. “However, it is unlikely that EsxE and EsxF are sufficient for TNT secretion, since an energy source is required in all known bacterial protein secretion systems. Therefore, it is possible that EsxE-EsxF associate with other proteins or protein complexes to achieve CpnT export and TNT secretion.”

The UAB researchers propose two models for the transport of CpnT by EsxE and EsxF. In the first, the EsxE-EsxF heterodimers form a pore in the inner membrane, and then form another pore in the outer membrane to create transmembrane channels. “Alternatively,” Niederweis said, “the inner membrane channel is extended to span the periplasm via filament formation, and connects to EsxE-EsxF pores in the outer membrane, exposing EsxF on the cell surface. In this model, the putative EsxE-EsxF channel tunnel enables export of the CpnT polypeptide to the outer membrane of M. tuberculosis, and subsequent secretion of TNT and EsxE-EsxF.”

Co-authors with Niederweis in the study, “Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis,” published in Nature Communications, are Uday Tak and Terje Dokland, UAB Department of Microbiology.
Brilliant, what? This is the sort of thing that any self-respecting ID advocate, such as Michael J Behe, could make another fortune from, with a book claiming it is 'irreducibly complex' so couldn't have evolved and must have been designed by a magic man, proving Darwin wrong. And all to make a million people get progressively more debilitated and sicker until they die. It used to be a lot more than that in the good ol' days before human medical science came up with antibiotics that kill the mycobacteria, but the Intelligent Designer is working on that problem too, and has already come up with antibiotic resistant strains which are becoming more common nowadays.

Creationist mode:


Well that's how a Creationist should be seeing things anyway, since they also purport to worship this putative entity they claim designed and created all living things and, being omniscient, knew exactly what they would do and designed them for that purpose.

Here is how people who understand biology see it:

Abstract


Mycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles into oligomers and long filaments, binds to membranes, and forms stable membrane-spanning channels. Electron microscopy of EsxEF reveals mainly pentameric structures with a central pore. Mutations of both WXG motifs and of a GXW motif do not affect dimerization, but abolish pore formation, membrane deformation and TNT secretion. The WXG/GXW mutants are locked in conformations with altered thermostability and solvent exposure, indicating that the WXG/GXW motifs are molecular switches controlling membrane interaction and pore formation. EsxF is accessible on the bacterial cell surface, suggesting that EsxEF form an outer membrane channel for toxin export. Thus, our study reveals a protein secretion mechanism in bacteria that relies on pore formation by small WXG proteins.

Perhaps the most amazing thing about ID Creationism is how it not only completely fails to provide any answers to basic questions about mechanisms, or provide any evidential basis for the claims it makes, but how it appears to blind its followers to the nasty realities of the natural world with it parasites and the suffering they cause, and the ultimate futility in the arms races which about and which make no sense at all as the product of a single master designer.

Amazingly too, they claim to get their morals from this hateful misanthropist!

As I showed in my beautifully-illustrated book, The Malevolent Designer: Why Nature's God is not Good, the natural world is full of examples such as this of how any designer who came up with it could only be a malevolent sadist who enjoys watching suffering and creates it for the pleasure of watching its creation suffer, like an evil man who breeds kittens for the fun of burning them alive and the pleasure of watchig them suffer.


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