Malevolent Designer News - How The Monkeypox Virus (MPVX) Was Redesigned To Make It More Contagious

Monkeypox virus

Monkeypox virus (MPXV)

New Research Defines Specific Genomic Changes Associated with the Transmissibility of the Monkeypox Virus | Mount Sinai - New York


Why did the monkeypox virus (MPXV) suddenly become much more contagious in 2022 to transform it from a relatively harmless, low-level infection of humans and other animals into a potential pandemic virus?

Scientists from Mount Sinai, New York, USA, in collaboration with researchers from the Carlos III Health Institute (ISCIII) in Madrid, Spain believe they have worked out the answer to this puzzle - a substantive change in the DNA virus' genome.

Creationists will reject the idea that this change was an evolutionary change driven by environmental selectors, despite the obvious explanation of the observed facts that this explanation offers because their cult dogma states that changes in genomes only happen if caused by their putative intelligent [sic] designer, although, to be fair to creationists, some of them will betray the religious nature of creationism by blaming viruses and these sorts of changes in their genomes on another creator, called 'Sin' to make it compliant with fundamentalist beliefs in a literal Bible.

But these apologists are continually undermined by those fundamentalists who generally, in their kind, caring and compassionate way, greet every new epidemic as their god's punishment for something they don't like. This will usually be some far-right political hobbyhorse in the USA, the way HIV was greeted with great jubilation by Christians as a 'Gay Plague', sent to punish homosexuals, and COVID-19 was declared to be God's punishment on New Yorkers for voting for Democrats.

However, those few creationists intelligent enough to realise they should be supporting the Discovery Institutes efforts to disguise creationism as science, will avoid these excuse, but they are then left with either evolution by natural selection, or intelligent [sic] design, so let's go with those who claim to see their god's hand in these viruses, so at least have managed to avoid the blasphemy of believing in two or more creators, while presenting their allegedly loving god as a pestilential malevolence.

Tell me all about the monkeypox virus, please. Monkeypox virus is a zoonotic virus that belongs to the Orthopoxvirus genus, which also includes the variola virus (the causative agent of smallpox), vaccinia virus (used in smallpox vaccine), and cowpox virus. It was first identified in 1958 when outbreaks of a pox-like disease occurred in monkeys kept for research, hence the name "monkeypox." Here are some key points about the monkeypox virus:

1. Transmission: Monkeypox primarily infects animals, especially rodents and primates, including monkeys. Humans usually acquire the virus through direct contact with infected animals or their bodily fluids (such as blood, respiratory secretions, or lesions) or through contact with contaminated objects. Human-to-human transmission is also possible, primarily through respiratory droplets or contact with skin lesions.
2. Symptoms: The symptoms of monkeypox in humans are similar to those of smallpox but are usually milder. They typically include fever, headache, muscle aches, and a generalized rash. The rash progresses through different stages, starting with flat, red lesions that eventually become raised and filled with fluid. The illness usually lasts for 2-4 weeks.
3. Geographical Distribution: Monkeypox is primarily found in Central and West African countries, particularly in forested regions. However, cases have also been reported outside Africa, including in the United States, Europe, and other parts of the world, usually due to travel-related or imported cases.
4. Treatment: There is no specific treatment for monkeypox, but supportive care can help manage symptoms. Antiviral medications, such as cidofovir, have shown some efficacy in treating severe cases.
5. Prevention: Vaccination is the most effective means of preventing monkeypox. The smallpox vaccine can provide cross-protection against monkeypox, although it is no longer routinely administered since smallpox has been eradicated. Researchers are also working on developing a specific monkeypox vaccine.
6. Recent Outbreaks: Monkeypox outbreaks have occurred sporadically over the years, with the largest outbreak recorded in the Democratic Republic of the Congo in 2017-2018. In recent years, there have been occasional reports of monkeypox cases in various countries, highlighting the ongoing risk of the virus.
7. Public Health Concerns: While monkeypox is generally considered less severe than smallpox, it can still pose a public health threat, especially in areas with limited healthcare infrastructure. Prompt detection, isolation of cases, contact tracing, and vaccination campaigns are essential for controlling outbreaks and preventing further spread of the virus.

Overall, while monkeypox is relatively rare compared to other infectious diseases, it remains a concern due to its potential for causing outbreaks, especially in vulnerable populations.

What the Mount Sinai-led team have discovered is the subject of an open access paper in the journal, Nature Communications and is explained in a Mount Sinai news item:

Mount Sinai scientists, in collaboration with researchers from the Carlos III Health Institute (ISCIII) in Madrid, Spain, have located and identified alterations in the monkeypox virus genome that potentially correlate with changes in the virus’s transmissibility observed in the 2022 outbreak. The findings were published April 18 in Nature Communications.

Monkeypox virus (MPXV) is a double-stranded DNA virus that can infect animals and humans. MPXV causes a disease known as mpox, with symptoms that include fever, swollen lymph nodes, and a rash. Most cases are mild and tend to get better on their own; however, mpox can be very painful and may lead to permanent scarring. First encountered in 1958 in crab-eating macaque monkeys imported to Belgium, MPXV has caused sporadic human disease outbreaks since the 1970s in Central and Western Africa. In May 2022, multiple countries, including the United States, reported an increasing number of MPXV infections and associated disease, including clusters in cases potentially linked to super-spreading events in Belgium, Spain, and the United Kingdom. While the number of new cases associated with the 2022 spillover has decreased over time, cases of the disease are still occurring among unvaccinated individuals, including a current increase in Central Africa due to a new spillover. As the virus’s circulation in humans increases, the risk of emergence of a more transmissible variant capable of becoming endemic in the human population increases.

Biopreparedness and virological surveillance involves studying the causes that favor zoonotic spillover and facilitates human-to-human transmission. When we observe significant changes in basic epidemiological features of a viral agent like monkeypox, it should reinvigorate our interest in understanding those transmission conditions. The increasing number of cases currently happening in Africa, and the 2022 epidemic, should be clear alert signals.

Professor Dr. Gustavo Palacios, PhD, senior author
Professor of Microbiology
Icahn School of Medicine
Mount Sinai, New York, USA.

To carry out the study, researchers analyzed samples from 46 patients infected with MPXV whose diagnosis and sequencing were carried out at the ISCIII at the beginning of the 2022 mpox outbreak. The team performed high-quality sequencing of each study participant’s complete monkeypox virus genome to determine possible correlations between genomic variations in the different groups of sequences and epidemiological links associated with the virus’s ability to evolve, transmit, and infect.

According to the research team, recurrent observed genomic changes were located in areas of the genome that could be related to viral adaptation. Those specific locations would contribute to modulating the viral replication cycle, adaptability, and path of entry and egress. These alterations appear in areas known as low complexity genomic regions, which are particularly difficult to sequence and analyze, explaining why they were overlooked before. This highly sophisticated complete genome sequencing was made possible through the use of two advanced sequencing technologies: single-molecule long-read sequencing (to cover highly repetitive regions) and deep short sequencing reads (to provide accuracy and depth).

By detailing the genomic alterations within these repetitive genomic sequences and linking them to critical viral functions, researchers provide a plausible explanation for the heightened transmissibility observed during the 2022 mpox outbreak.

These findings might be offering the first hints to help us understand the unique features of the strains associated with sustained human-to-human transmission, which has not ever been observed in these agents. Better understanding of the doors that facilitate transmission of viral agents and impact their clinical presentations will enable us to develop more effective prevention and treatment strategies.

Professor Gustavo Palacios

In the context of a DNA virus genome, what are 'tandem repeats'? In the context of a DNA virus genome, tandem repeats refer to specific sequences of nucleotides that are repeated one after another and are located adjacent to each other along the DNA strand. These repeats can vary in length, ranging from a few nucleotides to several thousand base pairs.

Tandem repeats can serve various functions within the viral genome, including:

1. Regulatory Elements: Tandem repeats can function as regulatory elements involved in the control of gene expression. Certain repeat sequences may serve as binding sites for regulatory proteins, transcription factors, or other molecules that modulate the activity of nearby genes.
2. Structural Elements: In some cases, tandem repeats contribute to the structural organization of the viral genome. They may form secondary structures, such as hairpin loops or cruciforms, which can influence genome stability, replication, or packaging.
3. Variability and Evolution: Tandem repeats can contribute to genetic variability within viral populations. The expansion or contraction of repeat sequences through processes like slipped-strand mispairing or recombination can lead to genetic diversity, which may affect viral fitness, virulence, or host adaptation.
4. Diagnostic Markers: Tandem repeats can serve as molecular markers for viral strain typing or epidemiological studies. The variability in repeat length or sequence among different viral isolates can be exploited for genotyping and tracking the spread of specific viral strains during outbreaks or transmission events.

Overall, tandem repeats are important structural and functional elements of DNA virus genomes, with diverse roles in gene regulation, genome organization, genetic variability, and epidemiology. Their presence and characteristics can provide insights into the biology and evolution of DNA viruses and may have implications for diagnostics, vaccine development, and antiviral therapy.

Technical detail and background to the research are given in the abstract and introduction to the team's paper in Nature Communications:

Abstract

The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly caused by genomic changes in subclade IIb MPXV. Key genomic changes could occur in the genome’s low-complexity regions (LCRs), which are challenging to sequence and are often dismissed as uninformative. Here, using a combination of highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204, and OPG208, could be affected in a manner consistent with the established “genomic accordion” evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability.

Introduction

Monkeypox virus (MPXV) is a double-stranded DNA virus classified in genus Orthopoxvirus (varidnavirian Nucleocytoviricota: Poxviridae: Chordopoxvirinae) along with other viruses, such as vaccinia virus (VACV) and variola virus (VARV) that also can infect humans¹. MPXV causes “monkeypox (mpox)” (World Health Organization International [WHO] Classification of Diseases, Eleventh Revision [ICD-11] code 1E71)².

First encountered in 1958 in crab-eating macaques imported to Belgium³, MPXV has caused sporadic human disease outbreaks since the 1970s in Eastern, Middle, and Western Africa, totaling approximately 25,000 cases (case fatality rate 1–10%)⁴, and also sporadic disease outbreaks among wild monkeys and apes^5,6. Exposure to MPXV animal reservoirs, in particular rope squirrels and sun squirrels, is a significant risk factor of human infections⁷.

Since May 2022, multiple European countries have reported a continuously increasing number of MPXV infections and associated disease, including clusters of cases associated with potential superspreading events in Belgium, Spain, and the United Kingdom (UK). As of January 10, 2024, a total of 94,274 cases had been reported in 118 countries/territories/areas in all six WHO regions. While the number of new cases has decreased over time, cases of the disease are still occurring among vaccinated individuals. Therefore, as the duration of the virus’s circulation in humans increases, the risk of emergence of a more transmissible variant capable of causing larger outbreaks escalates.

Phylogenetically, historic MPXV isolates cluster into two clades⁸, designated I and II^9,10. Clade I viruses are considered more virulent and transmissible than clade II viruses^8,9,11. The viruses of the 2022 epidemic belong to subclade IIb^12,13,14, a line of descent of MPXV that had been circulating in Nigeria, likely since 1971¹⁵.

The clinical presentation of mpox caused by MPXV clade I or subclade IIa includes fever, headache, lymphadenopathy, and/or malaise, followed by a characteristic rash that progresses centrifugally from maculopapules via vesicles and pustules to crusts that may occur on the face, body, mucous membranes, palms of the hands, and soles of the feet¹⁶. The clinical presentation of subclade IIb infection diverges from classical mpox by having a good prognosis, self-limiting but infectious skin lesions (typically emerging at and restricted to the genital, perineal/perianal, and/or peri-oral areas) before the development of fever, lymphadenopathy, and malaise. Generalized disease usually manifests with a rash that has not been widely observed in the current outbreak. Human-to-human transmission is substantially higher in outbreaks associated with subclade IIb MPXV than those caused by clade I and subclade IIa^{17,18,19,20,21}. The R₀ for MXPV IIb among men who have sex with men (MSM) is higher than 1. Transmission may be catalyzed by a decrease in protection associated with the VARV/smallpox vaccination campaign that ended in 1980^22,23. Furthermore, a change in transmission route may be the cause of the difference in clinical presentation and pathogenesis as was shown in animal models²⁴.

Orthopoxvirus infections are classified as systemic or localized²⁵. The involved orthopoxvirus and the immune status of the host are determinants of generalized or localized infection. Different mechanisms of virion entry and egress, as well as virus-encoded host restriction factors, also play pivotal roles in determining the clinical manifestation of infection^{26,27,28,29,30}. Localized usually means that signs are restricted to the site of viral entry, which is the most common clinical presentation described in the 2022 mpox outbreak. Changes in the genome of the current MPXV variant, such as gene loss³¹ may explain both trends.

The MPXV genome is a linear, ≈197-kb-long double-stranded DNA with covalently closed hairpin ends. The genome’s densely packed orthologous poxvirus genes (OPGs)³² are distributed over a central conserved region (“core”) and flanking terminal regions, each of which ends in identical but oppositely oriented ≈6.4-kb-long terminal inverted repetitions (ITRs). Roughly 193 open reading frames (ORFs) encode proteins with ≥60 amino-acid residues. “Housekeeping” proteins involved in MPXV transcription, replication, and virion assembly are encoded by OPGs located in the central conserved region, whereas proteins involved in host range and pathogenesis are mostly encoded by OPGs located in the terminal regions³³. Like all orthopoxvirus genomes, the MPXV genome contains numerous tandem repeats in the ITRs as well as nucleotide homopolymers all over the genome^33,34,35,36. However, other similar structures through the MPXV genome were observed in the form of short tandem repeats (STRs). Moreover, initial observations appear to indicate that these STRs (which may consist of dinucleotide, trinucleotide, or more complex palindromic repeats) are localized in areas where more variation is observed, suggesting a crucial role in MXPV biology and evolution.

Orthopoxviruses rapidly acquire higher fitness by massive gene amplification (genome expansion) when encountering severe bottlenecks in vitro. This amplification, akin to gene reduplication in organismal evolution, enables gene copies to accumulate mutations, potentially resulting in protein variants that can overcome the bottlenecks. Subsequent gene copy reduction (genome contraction) offsets the costs associated with increasing genome length, thereby retaining the adaptive mutations³⁷. Orthopoxviruses also rapidly adapt to selective pressures by single-nucleotide insertions (genome expansion) or deletions (genome contractions) within poly-A or poly-T stretches, resulting in easily reversible gene-inactivating or re-activating frameshifts³⁸. These rhythmic genome expansions and contractions are referred to as “genomic accordions” at the gene and base level³⁷. Given the overall conservation of STRs in orthopoxvirus genomes, we hypothesized that their variation could be a third type of genomic accordion and that, overall, this type of adaptation (which we designate here as low-complexity regions [LCRs]), rather than single-nucleotide polymorphisms (SNPs), could be the key to understanding the unusual epidemiology of 2022 subclade IIb MPXV. We do not know whether this different epidemiology is due intrinsically to the virus, to different host behavior, and/or different transmission routes, but all should influence the composition of the MPXV genome, as different selective and purifying pressures would necessarily leave marks on the affected viral effectors.

In this study, we provide a comprehensive genomic characterization of LCRs during the mpox outbreak. Our analysis establishes the fact that LCRs exhibit a non-random distribution across the genome. Moreover, we demonstrate that LCRs display higher entropy compared to SNPs. Importantly, our findings highlight three specific gene candidates that warrant further investigation in relation to transmissibility and/or adaptation. As a result, we propose a focused examination of LCR variability in future MPXV genomic analyses. The distinctive characteristics observed in LCRs emphasize their potential significance in understanding the dynamics of the currently circulating viral clades and suggest promising avenues for targeted research.

Fig. 1: De novo assembly of subclade IIb lineage B.1 monkeypox virus (MPXV) genome sequence 353R.

A visual representation of the fully annotated MPXV isolate 353R genome (based on the subclade IIb lineage A reference isolate MPXV-M5312_HM12_Rivers genome sequence annotation). Shown are (from the outside to the inside): high-quality genome (HQG) hybrid assembly (wide outer light blue ring); sequencing coverage distribution graph (thin ragged line [green: ≥10,000x, 99.42%; black: 1000x–10,000, 0.28%; orange: <1000x–10, 0.1%; red: <10–0, 0.2%]); orthologous poxvirus gene (OPG) annotations according to the standardized nomenclature³² (lettering and shaded boxes [orange: ANK/PRANC (N-terminal ankyrin protein with PRANC domain) inverted terminal repetition [ITR] regions; gold: Bcl-2 domain; blue: BTB/Kelch domains; green: housekeeping; purple: other; pink: TNFR and/or PIE domains); contigs from NovaSeq, MiSeq, and nanopore sequencing (wide inner gray rings). Additionally, radial lines and shading that originate in the center and reach outward on the white background indicate low-complexity regions (LCRs; royal blue) and areas with more change (light blue).

I wonder if a creationist can explain this apparent redesign of the monkeypox virus to make it more transmissible. Is it the work of:

1. 'Sin', which implies a second, rival, designer god over whom creationism's god has no power?
2. Creationism's putative intelligent designer, which implies pestilential malevolence rather than omni-benevolence?
3. A mindless, natural, evolutionary process in which nothing supernatural was involved?

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