Malevolent Design - No Fun For Creationists As The Candida Family of Fungi Are Evolving To Keep Infecting Us

A Candida albicans cell forming a hyphal extension

Candida auris causes multidrug-resistant infections that can result in organ failure

Credit: Kateryna Kon/Science Photo Library

Candida evolution disclosed: new insights into fungal infections | IRB Barcelona

The Candida genus of fungi are related to yeasts (i.e., single-celled fungi) but are specialists at living in or on our bodies and are common infections in body cavities such as the mouth, anus, vagina and urethra and the genito-urinary and respiratory tract, and other moist areas like armpits, inner surfaces of joints like the elbow and knee, groins and fold beneath breasts and buttocks.

They can also become systemic infections causing organ failure and death, especially in people who are immune compromised for any reason. So, they are a threat to people who are in generally poor health, who have had transplants and need to take immunosuppressive drugs, or people receiving chemotherapy for cancer.

And, like some bacterial pathogens, they are good at evolving immunity to anti-fungal medication.

One species, Candida auris, has evolved multiple drug resistance and is now a serious threat to people in hospital for other conditions.

Now, a research group from the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Supercomputing Center - Centro Nacional de Supercomputación (BSC-CNS), led by the ICREA researcher Dr. Toni Gabaldón, has identified hundreds of genes subject to recent, clinically-relevant selection in six species of the fungal pathogen Candida. In other words, the genes that have given Candida species their clinically-relevant drug resistance.

First a little AI background to the Candida genus:

Tell me all about the different species of Candida fungi and what they cause, please. Candida is a genus of yeast fungi that includes various species, some of which are part of the normal microbiota in humans and other animals. However, under certain conditions, Candida species can cause infections, particularly in individuals with weakened immune systems or other predisposing factors. Here are some key Candida species and the types of infections they commonly cause:

1. Candida albicans:
   • Common Infections: Candida albicans is the most common and well-known species. It is a part of the normal flora in the mouth, gastrointestinal tract, and genital area. However, it can cause infections such as oral thrush, vaginal yeast infections, and invasive candidiasis (bloodstream infection) in individuals with compromised immune systems.
2. Candida glabrata:
   • Characteristics: Candida glabrata is another important species, known for its ability to cause infections and its resistance to some antifungal medications.
   • Common Infections: It is often associated with urinary tract infections, bloodstream infections, and infections in other mucous membranes.
3. Candida parapsilosis:
   • Common Infections: Candida parapsilosis is frequently associated with infections in individuals with indwelling medical devices, such as catheters. It can cause bloodstream infections and infections in the nails.
4. Candida tropicalis:
   • Common Infections: Candida tropicalis can cause a range of infections, including bloodstream infections and infections in the urinary tract, respiratory tract, and other mucous membranes.
5. Candida krusei:
   • Characteristics: Candida krusei is often less susceptible to certain antifungal drugs.
   • Common Infections: It can cause infections in individuals with weakened immune systems, such as bloodstream infections and infections in the gastrointestinal and genitourinary tracts.
6. Candida auris:
   • Characteristics: Candida auris has gained attention as an emerging multidrug-resistant species.
   • Common Infections: It is associated with invasive infections, particularly in healthcare settings. Candida auris can cause bloodstream infections, wound infections, and infections in various body sites.

It's important to note that while Candida species are part of the normal microbial community, overgrowth or infections can occur in certain conditions. Factors such as immunosuppression, antibiotic use, diabetes, and other underlying health conditions can contribute to the development of Candida infections. Treatment typically involves antifungal medications, but drug resistance is an increasing concern, particularly with certain species like Candida auris. If you suspect a Candida infection, it is crucial to consult with a healthcare professional for an accurate diagnosis and appropriate treatment.

Drug resistance in pathogens has been a problem for creationists who have more than a superficial understanding of biology, ever since their guru and Deception Institute leading light, Michael J Behe, provided them with what they wave around a 'proof' that their god exists, by writing a book telling them the E. coli flagellum must have been intelligently designed because he didn't know how it could have evolved (because he hadn't read the accounts in the available literature). He then compounded this problem for them by writing another book telling them anti-malarial drug resistance in Plasmodium falciparum must have been intelligently designed (because he couldn't do the simple maths needed to model an evolutionary process in a population - or knew his target marks would be able to).

This means creationists are now stuck with either rejecting Behe's 'proof of God' and blaming 'Sin’ or sticking with Behe and letting their favourite god take the blame for pathogens and how they become drug resistant to continue to cause suffering in the world, in an arms race with medical science.

So how did drug resistance evolve in Candida? An Institute for Research in Biomedicine (IRB Barcelona) news release explains the research:

Candida evolution disclosed: new insights into fungal infections

• Identification of genes under recent selection provides insights into the molecular mechanisms of human-related adaptation in Candida pathogens.
• The study reveals both known and novel genetic variants associated with drug resistance, offering potential targets for improved antifungal therapies.
• The work by IRB Barcelona’s Comparative Genomics lab has been published in the journal Nature Microbiology.

Global fungal infections, which affect one billion people and cause 1.5 million deaths each year, are on the rise due to the increasing number of medical treatments that heighten vulnerability. Patients undergoing chemotherapy or immunosuppressive treatments after organ transplant often present compromised immune systems. Given the emergence of resistant strains, the limited variety of current antifungal drugs as well as their cost and side effects, the treatment of these infections is challenging and brings about an urgent need for more effective treatments.

In this context, a team from the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Supercomputing Center - Centro Nacional de Supercomputación (BSC-CNS), led by the ICREA researcher Dr. Toni Gabaldón, has identified hundreds of genes subject to recent, clinically-relevant selection in six species of the fungal pathogen Candida.

“This work highlights how these pathogens adapted to humans and antifungal drugs and provides valuable knowledge that could lead to better treatments for Candida infections,” explains Dr. Gabaldón, head of the Comparative Genomics lab at IRB Barcelona and the BSC.

More than 2,000 genomes from 6 different species

The study delves into the evolutionary landscape of Candida pathogens by analysing approximately 2,000 genomes from clinical samples of six major Candida species. These genomes are stored in public databases. The researchers compared these genomes to a reference, creating a comprehensive catalogue of genetic variants.

Building on previous work addressing drug-resistant strains, the researchers conducted a Genome-Wide Association Study (GWAS) to identify genetic variants linked to antifungal drug resistance in clinical isolates. This approach provided insights into both known and novel mechanisms of resistance towards seven antifungal drugs in three Candida species. “Additionally, a concerning finding has arisen from the study: the potential spread of resistance through mating between susceptible and resistant strains, contributing to the prevalence of drug-resistant Candida pathogens,” explains Dr. Miquel Àngel Schikora-Tamarit, a postdoctoral researcher in the same lab and first author of the study.

In addition, by focusing on variants acquired recently among clinical strains, the researches detected shared and species-specific genetic signatures of recent selection that inform on which adaptations might be needed to thrive and spread in human-related environments.

Beyond the novel insights into the adaptation of Candida, the study provides a valuable resource, namely a comprehensive catalogue of variants, selection signatures, and drivers of drug resistance. This knowledge not only contributes to our understanding of these infections but also lays the groundwork for future experiments and potential advancements in the development of more effective treatments for Candida infections.

Technical detail is given in the team's open access paper in Nature Microbiology:

Abstract

Understanding how microbial pathogens adapt to treatments, humans and clinical environments is key to infer mechanisms of virulence, transmission and drug resistance. This may help improve therapies and diagnostics for infections with a poor prognosis, such as those caused by fungal pathogens, including Candida. Here we analysed genomic variants across approximately 2,000 isolates from six Candida species (C. glabrata, C. auris, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis) and identified genes under recent selection, suggesting a highly complex clinical adaptation. These involve species-specific and convergently affected adaptive mechanisms, such as adhesion. Using convergence-based genome-wide association studies we identified known drivers of drug resistance alongside potentially novel players. Finally, our analyses reveal an important role of structural variants and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Our results provide insights on how opportunistic pathogens adapt to human-related environments and unearth candidate genes that deserve future attention.

Main

Fungal infections pose a serious health threat, affecting more than one billion people and causing approximately 1.5 million deaths each year^1,2. The problem is growing due to insufficient diagnostic and therapeutic options^3,4, increasing numbers of susceptible patients^1,5, the expansion of pathogens partly linked to climate change^6,7 and the alarming rise of antifungal drug resistance^4,8,9. Candida species are a major cause of severe hospital-acquired infections¹, prompting the classification of some species (Candida auris, Candida albicans, Candida glabrata, Candida tropicalis and Candida parapsilosis) as critical or high-priority targets by the World Health Organization².

A promising strategy to improve current therapies is to understand the evolutionary mechanisms of adaptation to antifungal drugs as well as to the human host. Candida pathogens have highly dynamic genomes (both within species^10,11,12 and within patient^13,14), which probably underlie these adaptive processes^{13,15,16,17,18}. For example, in vitro evolution studies have pinpointed genome-wide changes underlying drug resistance^19,20,21. In addition, analyses of serial clinical isolates^13,14, genome-wide association studies (GWAS)^22,23 and population genomics research^11,12,24 have partially clarified the clinical relevance of resistance mechanisms. Similarly, directed evolution experiments in mice^25,26,27, the analysis of paired clinical isolates¹³ and population genomics studies^12,28 have explored host adaptation mechanisms involving virulence, adhesion or filamentous growth. Furthermore, some studies used ratios between non-synonymous and synonymous variation (such as πN/πS) to infer signatures of selection, which are useful to predict genes involved in clinical adaptation where the relevant phenotypes (such as drug susceptibility or cell adhesion within a patient) are not measurable^12,29,30,31.

However, our understanding of how Candida species adapt in a clinical context is limited due to many reasons. First, most clinical studies include small sample sizes and/or lack rigorous statistical testing of the associations between genotypes and adaptive changes. Second, most studies involve only C. albicans, leaving open questions in other species². Third, despite the importance of structural variants (SVs; such as deletions, duplications, inversions and/or translocations; Fig. 1)^32,33,34, their contribution to clinically relevant adaptation remains largely unexplored. Fourth, similarities in adaptation mechanisms across species remain elusive because most studies focus on only one species and use different methods. This is key to understanding the epidemiology of these pathogens as well as enabling personalized treatments and prevention strategies. Fifth, many exploratory clinical studies focus only on known adaptive mechanisms (that is, known drug-resistance genes, as discussed previously²³), which means that there may be unexplored factors. Finally, current studies of selection consider all variants within a gene, which may reflect ancient adaptation unrelated to the clinics. It may be important to only analyse recently emerged variants, as they are more likely to reflect clinically relevant selective pressures (as proposed in ref. ³⁵).

Fig. 1: A genome dataset to study recent evolution across major Candida species.

a, Overview of the data-generation process. To study the genome-wide signs of recent selection and drug resistance, we processed available whole-genome sequencing datasets from the National Center for Biotechnology Information Sequence Read Archive (NCBI SRA) for C. glabrata, C. auris, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. We used these data to identify SNPs, indels, CNVs and SVs in each strain. In addition, we manually curated the associated literature to obtain antifungal drug-susceptibility data and information about the type of strain (that is, clinical or environmental). WGS, whole-genome sequencing. b, SNP-based trees for all strains of each species (Methods). The size of each tree is proportional (in logarithmic scale) to the number of strains (indicated in parentheses). The clades inferred here are represented in different colours in the branches and outer strips. Symbols were used to indicate how each clade overlaps with clades defined in other recent population studies (C. albicans²⁸, C. auris¹¹, C. glabrata¹², C. tropicalis²⁴ and C. orthopsilosis³⁶): =, known (one-to-one match); *, new; and X, inconsistent (it is inconsistent with previous clade definitions; Methods). Supplementary Table 1 includes all the clade definitions as well as the trees in Newick format. The inner strip represents the type of strain, where ‘other’ refers to strains with engineered genomes or strains resulting from directed evolution experiments. In this inner strip, the width of each colour indicates the number of strains of each type in each clade but they are not displayed in the order of the tree. Branches with support < 95 were collapsed. The species tree (top) was obtained using OrthoFinder. c, Variant types identified in this study. Structural variants are complex rearrangements identified with a breakpoint-detection algorithm, whereas CNVs are variants generating large duplications and deletions inferred from changes in coverage (Methods).

To address these gaps, we used approximately 2,000 available genomes from major Candida species to investigate two open questions in clinical adaptation. First, we used phylogenetics and πN/πS-inspired tools to infer the genes with signatures of recent and potentially clinically relevant selection in C. glabrata, C. auris, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. Second, we used convergence-based GWAS to infer the genomic drivers of resistance to echinocandins, polyenes and azoles in C. glabrata, C. auris and C. albicans. In both cases we measured the contribution of various variant types, including SVs. Our analyses revealed both expected and novel adaptive mechanisms, including those convergently acting in several species.

Schikora-Tamarit, M.À., Gabaldón, T.
Recent gene selection and drug resistance underscore clinical adaptation across Candida species.
Nat Microbiol 9, 284–307 (2024). https://doi.org/10.1038/s41564-023-01547-z

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)/div>

Of course the evolutionary explanation for these fungi is quite straightforward and doesn't need magic designers, good, bad or indifferent, but, because creationists have been conditioned to reject that explanation, and have been unwittingly driven into a corner where they must attribute it to their favourite designer god by Michale J Behe, they have no option but to accept the appearance of malevolence as the result of their god's design.

So, it's amusing to see creationists either admitting they are wrong (something they can never allow themselves to do) or committing the blasphemy of ascribing their god to an obviously malevolent design like drug-resistant pathological fungi.

This is what happens when you are fooled into subscribing to a counter-factual cult which is more concerned more with fleecing you blind than in guiding you toward the truth.

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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.

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