Rosa Rubicondior: Malevolent Design - The Sneak Tactics of Toxoplasma gondii

Toxoplasma gondii parasite uses unconventional method to make proteins for evasion of drug treatment

Here we are with yet another example of an organism that, if there is a designer behind it, that designer can only be described as malevolent and determined to maximise the suffering and misery in the world.

It is, of course, another example of a nasty little parasite which, if you subscribe to the creationist view that complexity 'proves' design, has been designed to ensure we are as vulnerable to is as possible by helping it evade the immune system and other mechanisms, supposedly designed by the same designer god to protect us from the parasites it designs to harm us.

This example is the parasite Toxoplasma gondii, which is notorious for manipulating its natural victims, which are felines and their prey species. For example, mice infected with T. gondii lose their fear of cats so they get eten and the parasite gets into its primary host; infected chimpanzees develop a liking for the smell of leopard urine.

Humans are not the natural secondary host, but the parasite readily infects us as we catch it from cats. It is thought that about one third of humans are infected. Once infected it is impossible to get rid of from the body because, even if antibodies are produced by our immune system, the parasites go into a dormant state as cysts which can form in any organs of the body, including the brain.

Toxoplasma gondii, it's evolution and its pathology in humans. Toxoplasma gondii: Overview, Evolution, and Pathology in Humans

Toxoplasma gondii is a protozoan parasite that infects warm-blooded animals, including humans, but primarily completes its life cycle in felines. It is a member of the phylum Apicomplexa, which includes other parasitic organisms such as Plasmodium (responsible for malaria). The parasite is notorious for its widespread prevalence and potential to cause severe disease in immunocompromised individuals and during pregnancy.
Evolutionary History

Toxoplasma gondii evolved from a common ancestor shared with other apicomplexans. Its evolutionary journey highlights adaptations for survival in both definitive (cat) and intermediate (other animals) hosts.

Apicomplexan Origin:

The phylum likely evolved from free-living photosynthetic algae.
The apicoplast, a remnant plastid, is a key organelle in T. gondii, crucial for fatty acid synthesis and other metabolic functions.

Host Adaptations:

Unlike its relatives with narrow host ranges, T. gondii evolved to infect a vast array of intermediate hosts. This adaptability is attributed to its ability to form hardy oocysts that can survive in the environment and tissue cysts that persist in hosts.

Clonal Lineages:

Population studies show three predominant clonal lineages (Types I, II, III), which emerged around 10,000 years ago, likely through a genetic bottleneck. These lineages exhibit differences in virulence and geographic distribution.

Lifecycle

Sexual Stage:

Occurs only in the intestines of felines, the definitive host. Cats excrete oocysts in their faeces.

Oocysts:

Environmentally resilient and infectious after sporulation, oocysts can contaminate food, water, and soil.

Intermediate Hosts:

Oocysts are ingested by other animals (e.g., rodents, birds, and humans). The parasite then forms tachyzoites (rapidly dividing forms) and bradyzoites (slowly dividing cyst forms) in tissues like the brain and muscles.

Transmission to Cats:

Cats are infected when they eat intermediate hosts harbouring tissue cysts, perpetuating the lifecycle.

Pathology in Humans

Humans typically acquire T. gondii through undercooked meat, contaminated water, or contact with infected cat faeces. Most infections are asymptomatic, but in certain populations, the parasite can cause significant disease.

Acute Toxoplasmosis:

Symptoms: Flu-like symptoms (fever, swollen lymph nodes, fatigue).
Immune response usually controls the infection, leading to cyst formation.

Latent Infection:

Tissue cysts persist, primarily in the brain and muscles, remaining dormant unless the immune system is compromised.

Immunocompromised Individuals:

Reactivation of latent infection can cause life-threatening conditions, such as toxoplasmic encephalitis, especially in individuals with HIV/AIDS or undergoing chemotherapy.

Congenital Toxoplasmosis:

If a woman acquires the infection during pregnancy, the parasite can cross the placenta, causing miscarriage, stillbirth, or severe congenital abnormalities (e.g., hydrocephalus, blindness, mental impairment).

Neurological and Behavioural Effects:

Emerging research suggests T. gondii might influence behaviour and mental health. It has been associated with altered risk-taking, neuropsychiatric disorders like schizophrenia, and changes in personality traits, though causation remains under investigation.

Diagnosis and Treatment

Diagnosis:

Serological tests detect specific IgM and IgG antibodies.
PCR assays can identify parasite DNA, particularly in congenital infections.

Treatment:

Acute infections: Combination therapy with pyrimethamine and sulfadiazine, supplemented with folinic acid to prevent folate depletion.
Chronic latent infections usually do not require treatment unless reactivated.

Control and Prevention

Hygiene: Proper handwashing after handling soil, cats, or raw meat.
Cooking Practices: Ensure meat is thoroughly cooked to destroy tissue cysts.
Cat Care: Regular cleaning of litter trays and preventing cats from hunting can reduce environmental contamination.
Toxoplasma gondii remains a fascinating and medically important organism due to its evolutionary ingenuity, widespread distribution, and complex interactions with hosts, including humans.

How they do this is the subject of a paper in the Journal of Biological Chemistry by researchers from Indian University School of Medicine and a news release by Indiana University.

Toxoplasma gondii parasite uses unconventional method to make proteins for evasion of drug treatment
A study by Indiana University School of Medicine researchers sheds new light on how Toxoplasma gondii parasites make the proteins they need to enter a dormant stage that allows them to escape drug treatment. It was recently published with special distinction in the Journal of Biological Chemistry.
Toxoplasma gondii is a single-celled parasite that people catch from cat faeces, unwashed produce or undercooked meat. The parasite has infected up to one-third of the world's population, and after causing mild illness, it persists by entering a dormant phase housed in cysts throughout the body, including the brain.

Toxoplasma cysts have been linked to behaviour changes and neurological disorders like schizophrenia. They can also reactivate when the immune system is weakened, causing life-threatening organ damage. While drugs are available to put toxoplasmosis into remission, there is no way to clear the infection. A better understanding of how the parasite develops into cysts would help scientists find a cure.

Through years of collaborative work, IU School of Medicine Showalter Professors Bill Sullivan, PhD, and Ronald C. Wek, PhD, have shown that Toxoplasma forms cysts by altering which proteins are made. Proteins govern the fate of cells and are encoded by mRNAs.

But mRNAs can be present in cells without being made into protein. We've shown that Toxoplasma switches which mRNAs are made into protein when converting into cysts.

Professor William J. Sullivan Jr., Corresponding author
Department of Pharmacology & Toxicology
Indiana University School of Medicine
Indianapolis, Indiana, USA.
Lead Author Vishakha Dey, PhD, a postdoctoral fellow at the IU School of Medicine and a member of the Sullivan lab, examined the so-called leader sequences of genes named BFD1 and BFD2, both of which are necessary for Toxoplasma to form cysts.

mRNAs not only encode for protein, but they begin with a leader sequence that contains information on when that mRNA should be made into protein.

Dr. Vishakha Dey, lead author.

Department of Pharmacology & Toxicology
Indiana University School of Medicine
Indianapolis, Indiana, USA.
All mRNAs have a structure called a cap at the beginning of their leader sequence. Ribosomes, which convert mRNA into protein, bind to the cap and scan the leader until it finds the right code to begin making the protein.

What we found was that, during cyst formation, BFD2 is made into protein after ribosomes bind the cap and scan the leader, as expected. But BFD1 does not follow that convention. Its production does not rely on the mRNA cap like most other mRNAs.

Dr. Vishakha Dey.

The team further showed that BFD1 is made into protein only after BFD2 binds specific sites in the BFD1 mRNA leader sequence. Sullivan said this is a phenomenon called cap-independent translation, which is more commonly seen in viruses.
Finding it in a microbe that has cellular anatomy like our own was surprising. It speaks to how old this system of protein production is in cellular evolution. We're also excited because the players involved do not exist in human cells, which makes them good potential drug targets.

Professor William J. Sullivan Jr.
The Journal of Biological Chemistry featured the new study as an "Editor's Pick" paper, which represent a select group of the journal’s publications judged to be of exceptionally high quality and broad general interest to their readership.

This paper describes a mechanism by which a parasite that causes toxoplasmosis in humans can respond to stress and allow the parasite to thrive. The discovery of this mechanism provides a basis for treating these infections. Moreover, a similar mechanism is important in cancer, suggesting that it may be a therapeutic target for multiple human diseases.

Professor George N. DeMartino, PhD, associate editor of the Journal of Biological Chemistry
University of Texas Southwestern Medical Center.

Additional co-authors on the study include IU School of Medicine's Michael Holmes, PhD, and Matheus S. Bastos, PhD. The work was funded by the National Institutes of Health and the Showalter Foundation.

Translational control mechanisms modulate the microbial latency of eukaryotic pathogens, enabling them to evade immunity and drug treatments. The protozoan parasite Toxoplasma gondii persists in hosts by differentiating from proliferative tachyzoites to latent bradyzoites, which are housed inside tissue cysts. Transcriptional changes facilitating bradyzoite conversion are mediated by a Myb domain transcription factor called BFD1, whose mRNA is present in tachyzoites but not translated into protein until stress is applied to induce differentiation. We addressed the mechanisms by which translational control drives BFD1 synthesis in response to stress-induced parasite differentiation. Using biochemical and molecular approaches, we show that the 5′-leader of BFD1 mRNA is sufficient for preferential translation upon stress. The translational control of BFD1 mRNA is maintained when ribosome assembly near its 5′-cap is impaired by insertion of a 5′-proximal stem-loop and upon knockdown of the Toxoplasma cap-binding protein, eIF4E1. Moreover, we determined that a trans-acting RNA-binding protein called BFD2/ROCY1 is necessary for the cap-independent translation of BFD1 through its binding to the 5′-leader. Translation of BFD2 mRNA is also suggested to be preferentially induced under stress but by a cap-dependent mechanism. These results show that translational control and differentiation in Toxoplasma proceed through cap-independent mechanisms in addition to canonical cap-dependent translation. Our identification of cap-independent translation in protozoa underscores the antiquity of this mode of gene regulation in cellular evolution and its central role in stress-induced life-cycle events.

Abbreviations

AP2apetala-2BFD1Bradyzoite Formation Deficient-1BRBinding RegionCDSprotein-coding sequenceFLucfirefly luciferaseNLucNano luciferaseRLURelative Luciferase UnitsuORFsupstream open reading frames

Cellular adaptation and differentiation processes in response to cellular stresses are initiated by reprogramming of gene expression. A central feature of this reprogramming is the rapid lowering of global protein synthesis in favor of selective translation of a subset of mRNAs that include transcription factors that activate genes for stress remediation or differentiation (1, 2, 3). We have shown that this paradigm governs life cycle stage transitions in protozoan parasites that underlie transmission and pathogenesis of infectious disease (3, 4, 5). The study of translational control in these early-branching eukaryotes not only promises to reveal potential novel drug targets but also sheds important mechanistic insights into the evolutionary origins of these regulatory processes (6, 7, 8).

Toxoplasma gondii is an obligate intracellular parasite of warm-blooded animals that causes opportunistic disease in humans. Upon ingestion, the parasites transform into a rapidly replicative stage (tachyzoite) that disseminates throughout the host body before converting into a quiescent stage (bradyzoite) housed in tissue cysts that can be sustained for the life of the host. Tissue cysts are a major route of transmission through the consumption of raw or undercooked meat (9). Reactivation of bradyzoites can occur when patients become immunocompromised, producing life-threatening damage to critical areas where tissue cysts typically reside, such as the brain, heart, and skeletal muscle (10). Current treatments of toxoplasmosis only target replicating tachyzoites and do not appear to exert appreciable activity against the formation or viability of tissue cysts (11). The formation of latent tissue cysts allows Toxoplasma to persist in its host and prevents a radical cure of this infection.

Given the importance of bradyzoites in driving parasite transmission and chronic disease, much research is aimed at understanding the molecular mechanisms orchestrating the conversion between tachyzoites and bradyzoites (12). Differentiation between life cycle stages requires the reprogramming of gene expression, while chromatin remodeling machinery and several apetala-2 (AP2) factors have been shown to contribute to the transcription of bradyzoite-inducing genes (13). Recently, Lourido and colleagues identified a “master regulator” transcription factor termed BFD1 (Bradyzoite Formation Deficient-1) that is necessary and sufficient for bradyzoite formation (14).

BFD1 is a SANT/Myb-like DNA-binding protein whose mRNA is present in tachyzoites but not translated until parasites are exposed to a bradyzoite-induction stress (14). We previously suggested with polysome profiling that BFD1 mRNA is preferentially translated when tachyzoites are subjected to a stress that induces bradyzoite differentiation (15). These studies indicate that expression of BFD1 protein is predominantly regulated by translational control and the elevated levels of BFD1 are sufficient to confer transcription events directing cyst formation. Consistent with this idea, the 5′-leader sequence of BFD1 mRNA is about 2.7 kb in length, harboring multiple predicted upstream open reading frames (uORFs), which are known in other model systems to regulate start codon selection and translation efficiency of the protein-coding sequence (CDS) (16). Moreover, a CCCH-type zinc finger mRNA-binding protein called BFD2 (also referred to as ROCY1) has recently been described that is suggested to direct the stress-dependent translation of BFD1 (17, 18).

Bulk cellular translation begins with eIF4F association with the 5′-cap of mRNAs through its eIF4E subunit, which then recruits the ribosomal preinitiation complex that proceeds to scan the 5′-leader for an optimal start codon (19). This cap-dependent translation can be modulated by uORFs that can be bypassed by scanning ribosomes or allow for re-initiation for efficient CDS translation (20). Cap-independent mechanisms have also been described, most commonly among viruses and less frequently for cellular mRNAs (21, 22, 23). Translation that can occur independent of eIF4E cap association and the subsequent ribosome scanning typically involves direct entry of ribosomes onto the 5′-leader sequence by secondary structures that interface with trans-acting proteins to recruit initiating ribosomes (22, 23).

In this study, we addressed the mechanisms of preferential translation of BFD1 during stress-induced bradyzoite differentiation. Utilizing luciferase reporter assays and genetically modified Toxoplasma parasites, we show that BFD1 translation can occur through a cap-independent mechanism that involves BFD2 binding to the 5′-leader sequence. By comparison, preferential translation of BFD2 during stress occurs by cap-dependent processes. Our results represent the first evidence of cap-independent translation in protozoa, suggesting that it is an ancient mechanism of gene regulation present in early-branching eukaryotes and is critical for directing differentiation in the Toxoplasma life cycle.

We can, of course, dismiss Michael J. Behe's biologically nonsensical excuse of 'devolution' from some presupposed initial perfection because any change which makes an organism better at producing descendants is classically evolutionary and it take mental gymnastics to a new hight of absurdity to believe that something better is less perfect than what preceded it.

So, as always, what creationists need to find the moral and intellectual courage to address is the question of evil and why their supposed creator creates these nasty little parasites that are responsible for so much suffering and misery in the world. Are they just the result of incompetent design or the malevolent design of an omnipotent, omniscient designer? Or are they the result of a mindless natural process?

Advertisement

Amazon