UTI's will affect 50% of women at some time in their lives
Despite their protestations that their god doesn't create pathogens - some other creative entity does that, apparently - they have been in love with Escherichia coli, or E. coli ever since their guru and Deception Insitute flunky, Michael J Behe, persuaded them that he had 'proved' their god exists and designs things because he couldn't work out how the E. coli flagellum could have evolved - so God did it!
There problem then, courtesy of Michael J Behe is that they have accepted that, if there was a designer involved in E. coli's design, it is the god that Michael J Behe 'proved' designed it, so their god designs pathogens, and even designs clever way to make them good at making us sick.
With that in mind, which creationist is going to argue against Michael J Behe's clever 'proof' that their god designs things so must exist, and insist that it isn't also behind the newly discovered way it manages to cause urinary tract infections (UTIs)?
The discovery that they can live, reproduce, and do their nasty thing in the otherwise near-sterile urinary tract, was made by researchers at the laboratory of Professor Harry Mobley in the University of Michigan Medical School.
Having been filtered by the kidneys, while urine contains some chemicals such as metabolites, it is about as sterile as it gets, with anything in it entering through the urethral meatus, in women, stupidly placed near the anus and inside the vulva where it can become infected during sexual intercourse by a penis cleverly designed with a foreskin to harbour pathogens under.
It has now been discovered that E. coli is also cleverly 'designed' to grab the nutrients it needs but can't manufacture itself by have a highly efficient transport system for taking them from its victims at a rate of thousands of molecules a second. One of the genes responsible for this, codes for an enzyme known as ATP-binding cassette (ABC).
Typical of creationism's 'intelligent' [sic] designer, if you believe in such a thing, is the Heath-Robinson workaround for the lack of genes for manufacturing these amino acids, where the parasite needs an energy-intensive ATP-based transport system, complete with multi-layered back-up systems to keep them working - the needless waste and needless complexity, so typical of evolved systems and the antithesis of intelligently designed systems. The researchers have published their findings, open access, in the journal PNAS and explained them in a University of Michigan news release:
A study reveals the important role of energy-producing transporters in bad bacteria that could be a new target for UTI therapies
Through a quirk of anatomy, women are especially prone to urinary tract infections, with almost half dealing with one at some point in their lives.
Scientists have been trying to figure out for decades how bacteria gain a foothold in otherwise healthy people, examining everything from how the microbes move inside and stick to the inside of the bladder to how they deploy their toxins to produce uncomfortable and often painful symptoms.
Research published in PNAS examines how the bacteria Escherichia coli, or E. coli—responsible for most UTIs—is able to use host nutrients to reproduce at an extraordinarily rapid pace during infection despite the near sterile environment of fresh urine.
Investigators working in the lab of Harry Mobley, Ph.D., at the University of Michigan Medical School began by looking at mutant strains that weren’t as good at replicating in mouse models to identify bacterial genes that may be important for establishing infection.
Doing so, they identified a group of genes controlling transport systems as critical.
Their previous gene expression screen revealed that nearly 25% of bacterial genes were dedicated to replication tactics including transport systems for specific amino acids, which E. coli use to bring in thousands of molecules per second, said Mobley.
First author Allyson Shea, Ph.D., a former member of Mobley’s lab and now assistant professor of Microbiology and Immunology at the University of South Alabama, cross referenced a library of transport proteins from E. coli against other species of UTI pathogens to see which were important for infection. She discovered that a type of transporter called ABC (for ATP-binding cassette) transporters appeared to be critical.
Then using organ agar made from the mouse urinary tract, she confirmed that ABC transporters were essential for infection. Many bacteria strains lacking these nutrient import systems were defective for growth on bladder and kidney organ agar.
The findings, Mobley notes, open avenues for the development of new therapeutics—which is especially important in an era of increasing antibiotic resistance.
Doing so won’t be easy, notes Shea, as bacteria have evolved multiple backups systems for this important class of transporters.
This subunit could potentially be a target to make the entire family of transporters dysfunctional.
While this wouldn’t necessarily replace antibiotics, she says, it could slow down growth so that antibiotics and the host immune system could do a better job at stopping the bugs.
Additional authors include Valerie S. Forsyth, Jolie A. Stocki, Taylor J. Mitchell, Arwen E. Frick-Cheng, Sara N. Smith, and Sicily L. Hardy.
Through a quirk of anatomy, women are especially prone to urinary tract infections, with almost half dealing with one at some point in their lives.
Scientists have been trying to figure out for decades how bacteria gain a foothold in otherwise healthy people, examining everything from how the microbes move inside and stick to the inside of the bladder to how they deploy their toxins to produce uncomfortable and often painful symptoms.
Research published in PNAS examines how the bacteria Escherichia coli, or E. coli—responsible for most UTIs—is able to use host nutrients to reproduce at an extraordinarily rapid pace during infection despite the near sterile environment of fresh urine.
Investigators working in the lab of Harry Mobley, Ph.D., at the University of Michigan Medical School began by looking at mutant strains that weren’t as good at replicating in mouse models to identify bacterial genes that may be important for establishing infection.
Doing so, they identified a group of genes controlling transport systems as critical.
When bacteria need something to grow, say an amino acid, they can get it in two ways. They can make it itself, or they can steal it from their host using what we call a transport system.
Professor Harry L. T. Mobley, co-author
Frederick G. Novy Distinguishes Professor of Microbiology and Immunology.
Department of Microbiology and Immunology
University of Michigan Medical School, Ann Arbor, MI, USA.
University of Michigan Medical School, Ann Arbor, MI, USA.
First author Allyson Shea, Ph.D., a former member of Mobley’s lab and now assistant professor of Microbiology and Immunology at the University of South Alabama, cross referenced a library of transport proteins from E. coli against other species of UTI pathogens to see which were important for infection. She discovered that a type of transporter called ABC (for ATP-binding cassette) transporters appeared to be critical.
Then using organ agar made from the mouse urinary tract, she confirmed that ABC transporters were essential for infection. Many bacteria strains lacking these nutrient import systems were defective for growth on bladder and kidney organ agar.
It appears bacteria make an investment into these energy expensive ATP transport systems in order to have a higher affinity for the energy sources they are interested in. These systems are very, very good at getting nutrients inside the cell.
Dr. Allyson E. Shea, lead author
Department of Microbiology and Immunology
University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Microbiology and Immunology
University of Michigan Medical School, Ann Arbor, MI, USA.
If you inhibit these transport systems, maybe you can inhibit the rapid growth of these bacteria.
Professor Harry L. T. Mobley.
What’s nice about this ATP-binding family is they all have an ATP binding subunit which gives the transport system the energy it needs to get nutrients across the cell membrane.
Dr. Allyson E. Shea.
While this wouldn’t necessarily replace antibiotics, she says, it could slow down growth so that antibiotics and the host immune system could do a better job at stopping the bugs.
Additional authors include Valerie S. Forsyth, Jolie A. Stocki, Taylor J. Mitchell, Arwen E. Frick-Cheng, Sara N. Smith, and Sicily L. Hardy.
So, we have yet another example from the world of microbial parasites where, if there is an intelligence behind the design, that intelligence must be malevolent. We can also rule out the creationist fallback of blaming another creator because the 'design' of E. coli is supposedly one of their best 'proofs' that their favourite god exists, and we can rule out their latest hobbyhorses, genetic entropy and 'devolution' [sic], because anything which improves a parasite's ability to live and replicate in its victim, can't possibly be presented as 'devolutionary' or the result of loss of some assumed original perfection.Significance
Transport is a vital process for survival across all domains of life. Employing multiple unbiased techniques, we show that the disruption of ATP-binding cassette (ABC) transporters leads to decreased fitness in uropathogenic Escherichia coli, the main causative agent of urinary tract infection. ABC transporters provide nutrients to the bacterial cell, requiring ATP. Loss of these systems leads to host-specific nutritional deficiencies that result in a dysregulation of virulence traits such as growth and motility. This highlights the overarching influence of bacterial transport and pleiotropic effects beyond bacterial metabolism. Deletion of multiple, specific, transcriptionally redundant systems leads to a decrease in murine colonization. Together, these findings extend our current knowledge of the cross-talk between bacterial metabolism and uropathogenic virulence mechanisms.
Abstract
Urinary tract infections (UTI) account for a substantial financial burden globally. Over 75% of UTIs are caused by uropathogenic Escherichia coli (UPEC), which have demonstrated an extraordinarily rapid growth rate in vivo. This rapid growth rate appears paradoxical given that urine and the human urinary tract are relatively nutrient-restricted. Thus, we lack a fundamental understanding of how uropathogens propel growth in the host to fuel pathogenesis. Here, we used large in silico, in vivo, and in vitro screens to better understand the role of UPEC transport mechanisms and their contributions to uropathogenesis. In silico analysis of annotated transport systems indicated that the ATP-binding cassette (ABC) family of transporters was most conserved among uropathogenic bacterial species, suggesting their importance. Consistent with in silico predictions, we determined that the ABC family contributed significantly to fitness and virulence in the urinary tract: these were overrepresented as fitness factors in vivo (37.2%), liquid media (52.3%), and organ agar (66.2%). We characterized 12 transport systems that were most frequently defective in screening experiments by generating in-frame deletions. These mutant constructs were tested in urovirulence phenotypic assays and produced differences in motility and growth rate. However, deletion of multiple transport systems was required to achieve substantial fitness defects in the cochallenge murine model. This is likely due to genetic compensation among transport systems, highlighting the centrality of ABC transporters in these organisms. Therefore, these nutrient uptake systems play a concerted, critical role in pathogenesis and are broadly applicable candidate targets for therapeutic intervention.
Fifty percent of women worldwide experience a urinary tract infection (UTI) at least once during their lives (1–3). UTIs are responsible for ~$5 billion a year in associated healthcare costs in the United States, making it the highest financial burden in kidney and urologic diseases (4–6). Of women visiting clinicians for a UTI, 95% do so for symptoms of cystitis (7). However, UTI range in severity because bacteria can ascend the ureters and cause acute pyelonephritis, elevating the risk of bacteremia, urosepsis, and fatality. Current treatment regimens of antibiotics are becoming increasingly ineffective due to rising resistance, it is therefore vital that we identify pathogen-specific therapies that target bacterial virulence (3, 8, 9). To understand bacterial genes important for infection, we constructed an ordered transposon library containing 2,419 unique gene mutants in prototype UPEC strain CFT073. This library was previously screened during experimental UTI to identify mutants that have significantly decreased fitness in the murine bladder (10). From 203 preliminary hits, we identified 20 clusters of orthologous genes and functional groups that are important for UPEC fitness during UTI. One such group was transporters, which composed nearly 25% of the identified fitness factors (10). These data suggest nutrient acquisition is a key determinant of UPEC urovirulence, thus prompting our independent, rigorous investigation into transport systems.
UPEC adherence, toxin activity, motility, and iron acquisition are well-studied virulence mechanisms (8, 11, 12), while bacterial energy acquisition strategies and metabolic flexibility have been historically understudied with respect to their role in virulence. However, our recent studies using RNA-seq on Escherichia coli in a UTI mouse model (13), and from human UTI (14), indicated that specific nutrient transporters are vital to UPEC within the urinary tract. While general bacterial biosynthetic pathways are repressed, import systems are induced (14) suggesting UPEC adopt a scavenging lifestyle during UTI relying on the consumption of host metabolites. We also know that the TCA cycle and gluconeogenesis, processes fueled by amino acids, are critical metabolic pathways utilized by UPEC during infection (15, 16). Collectively, these data from multifaceted studies provide strong evidence for the essential role of host-derived nutrients in fueling uropathogenesis.
There are six major transporter families annotated in UPEC including ATP-binding cassette (ABC) eukaryotic-like, ABC prokaryotic-like, phosphotransferase (PTS), major facilitator superfamily (MFS), solute carrier (SLC), and “Others” [KEGG, (17)]. We found that ABC prokaryotic-like uptake systems were the most critical for fitness in the ascending murine model of UTI using Tn-seq screening. The ABC eukaryotic-like transport systems in bacteria mainly act as efflux pumps to facilitate multidrug resistance (18–20) whereas the prokaryotic-like systems consist of a substrate-binding protein, permease, and an ATPase subunit (18). In addition to coupling ATP hydrolysis to transport substrates from the periplasm into the cytoplasm (21, 22), ABC systems can also regulate physiological processes both directly and indirectly (22–24). Unlike the other families of transporters, ABC prokaryotic-like transporters are generally encoded as polycistronic systems (24) and can contain multiple subunits that are able to form hetero- or homodimers (22, 23, 25). Due to the sequence variances between human and bacterial ABC systems, these could be potential targets for competitive pharmacological inhibition (25). Despite the wealth of literature on this family of transporters that spans the biological kingdoms, there are still several annotated but uncharacterized systems with unknown substrates.
We conducted an unbiased survey of all annotated transport systems of the type uropathogenic strain E. coli CFT073 (26, 27) to identify the most critical for the host-specific nutritional niche and infection-specific virulence in the host. We narrowed our focus to the family of ABC prokaryotic-like transporters, which were found to be highly conserved among both UPEC and other uropathogenic Gram-negative species. Deletion of ATP-driven transport systems caused severe growth defects and altered urovirulence phenotypes, such as motility. Finally, we determined that genetic redundancy of these transporters would require multisystem inhibition to significantly impede bacterial colonization of the urinary tract. For example, we found a quadruple mutant in highly redundant amino acid import systems necessary to achieve substantial fitness defects in vivo. Another critical advancement from this study was establishing a transporter hierarchy of which systems are favored during active UTI. Indeed, we found transporter hierarchy at the genetic level that showed primary upregulation of ABC systems. Together, these results posit that nutrient availability in the host niche is an important factor directly contributing to UPEC uropathogenic potential.
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
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.
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