Written by Emily Locke
Even the Vikings had smallpox – a fact scientifically proven for the first time by a research team led by Dr. Barbara Mühlemann of Charité Berlin. In a study published in 2020 in the prestigious scientific journal Science, the researchers analyzed DNA from Viking skeletons found in burial sites in Denmark, Norway, Sweden, Russia, and England [1]. Using modern molecular biology techniques, the team detected the variola virus, which causes smallpox, in bones up to 1,400 years old. This provided the first scientific evidence that the Vikings were infected with the smallpox virus [2]. Although the variola virus, considered the deadliest virus in history, was declared eradicated in 1980 following a global vaccination campaign, closely related animal poxviruses still circulate today. These viruses pose a risk of transmission from animals to humans.
In 2024, reports of new outbreaks of the mpox virus in Central and West Africa made headlines – a disease with comparable symptoms but lower mortality than smallpox. Infections with the mpox virus (MPXV) have also been detected in Germany, but the Robert Koch Institute (RKI) currently assesses the risk to the general population as low [3]. How does the virus behind mpox work? What symptoms does it cause, and how can we effectively protect ourselves? Could this disease pose a danger to Germany? And how can the Vikings help us better understand this virus?
1) Tracing the Origins of Mpox
2) Mpox – A Milder Variant of Smallpox?
3) Inside the MPXV – Understanding the Virus
4) Unexpected Genetic Diversity in Poxviruses
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The mpox virus was first discovered in 1958 by the Statens Serum Institute in Copenhagen in laboratory monkeys, hence the original name ‘monkeypox’ [4]. Although monkeys can be infected and fall ill, they are now considered accidental hosts – like humans. The actual reservoir of the virus in African endemic regions is believed to be squirrels and other rodents. In humans, the mpox virus was first identified in 1970 in the Democratic Republic of Congo in a 9-month-old boy. Since then, human cases of mpox have been reported primarily in West and Central African countries, including Nigeria, Cameroon, the Democratic Republic of Congo, and the Republic of Congo. Recently, cases have also been detected in East African countries such as Burundi, Rwanda, Uganda, and Kenya [5].
Mpox viruses are classified into genetic types called clades. Today, we distinguish between Central African Clade I and West African Clade II. Both clades have spread extensively across Africa. In spring 2003, mpox was detected in humans outside Africa for the first time. The outbreak was traced to the import of MPXV-infected rodents from Ghana to the United States. The virus likely spread initially to prairie dogs in pet stores and then to animal handlers and pet owners. Until spring 2022, only isolated cases were recorded outside Africa [5]. In May 2022, mpox Clade IIb cases were confirmed in Germany, and since summer 2023, cases have been consistently recorded at low levels.
Figure 1: Countries affected by the African mpox epidemic (Clade Ib) as of December 4, 2024 [7].
This year, however, a renewed surge of mpox was noted in several African countries, driven by Clade I mpox viruses, including a new variant, Ib (Fig. 1) [3]. Due to the increased fatality rate of this variant and the escalating spread of infections, the WHO declared a Public Health Emergency of International Concern (PHEIC) for mpox on August 14, 2024 [6]. This announcement is reminiscent of the COVID-19 pandemic, which also prompted a PHEIC declaration. Does this mean mpox might become the next global pandemic? In Germany, an mpox infection with the new Clade Ib variant, acquired abroad, was reported for the first time on October 18, 2024 (Fig. 1) [3]. However, the RKI reassures the public: the emergency currently remains confined to Central Africa, and there is no significant threat to the general population in Germany [3].
MPXV belongs to the poxvirus family and can cause skin changes similar to those caused by variola virus, which causes smallpox – such as rashes, blisters, pustules, wounds, and scabs (Fig. 2). These skin changes are often preceded or accompanied by general symptoms such as fever, headache, muscle and back pain, or swollen lymph nodes [8]. Fortunately, most cases are not severe; no deaths have been reported in Germany. Globally, case fatality rates are extremely low: during the Mpox Clade IIb outbreak, about 200 deaths were reported among over 100,000 cases [3]. Mpox typically resolves on its own within two to four weeks but can leave scars [8]. Treatment primarily addresses symptoms, but the antiviral drug Tecovirimat is approved for severe cases in the EU [5].
Figure 2: Mpox lesions on the arms and legs of a child. This 4-year-old girl was infected with MPXV in Bondua, Grand Gedeh County, Liberia [9].
Mpox spreads through close skin contact with the characteristic lesions, such as during cuddling or sexual activity. The fluid in the blisters, the secretions from the wounds, and the scabs that form after the blisters burst are particularly infectious. The virus can enter the body through mucous membranes, especially those involved in sexual activity, or through the skin. Mpox is typically diagnosed via skin lesion swabs or blood tests. Vaccination is the best protection against infection and severe illness. It is usually administered in two doses at least 28 days apart. Post-exposure vaccination is also possible within 14 days of contact [8]. The available vaccines are believed to be effective against both Clade I and Clade II [3].
The Mpox virus is an enveloped dsDNA virus from the Orthopoxvirus genus, measuring 220–450 nm in length and 140–260 nm in diameter (Fig. 3). Its genome is about 197 kb long and encodes approximately 200 proteins. The virus's ovular envelope contains compact regions known as lateral bodies. The intracellular, mature virus (MV) has a single membrane, while the extracellular, enveloped virus (EV) has two membranes, each embedded with distinct glycoproteins (Fig. 3) [4].
Figure 3: Diagram of the Mpox virus (MPXV). Cross-sections of the mature virion (MV) and the enveloped virion (EV) [10].
The extracellular form of the virus is taken up into the host cell via macropinocytosis, a clathrin-independent form of endocytosis, leading to the formation of vesicles in the cytoplasm. Fusion of the viral envelope with the vesicle membrane results in uncoating of the virus, which is then present in the cell as a mature virion. During this process, lateral bodies are released into the interior of the cell. These bodies contain specific proteins that induce immunomodulation in the host cell, thereby disabling cellular defense mechanisms against viral replication [11]. This enables the translation of viral mRNA into structural proteins, which assemble into new extracellular viruses necessary for cell-to-cell transmission [12].
All genes identified as essential for orthopoxviruses are also found in the mpox virus. These genes encode, among other things, growth factors and proteins necessary for immune evasion [13]. The concerning factor: the mutation rate of these genes is significantly higher than previously assumed. While earlier estimates suggested 1 to 2 gene mutations per year, recent molecular biological analyses of MPXV Clade II have identified around 50 single nucleotide polymorphisms (SNPs) compared to historical data from 2018/2019. These include changes in the surface glycoprotein B21, which is crucial for immune system recognition. The exact cause of this increased mutation rate remains unclear, but the host cell enzyme APOBEC3 may play a critical role [14]. Additionally, mpox viruses can incorporate nucleotide sequences from related viral strains through homologous recombination and foreign DNA through non-homologous recombination during coinfection [4].
At this point, we return to the Vikings: they can help us understand the genetic diversity of poxviruses. Sequencing the variola virus extracted from Viking skeletons revealed that the poxvirus from the 7th century was significantly different from today’s virus [2]. It exhibited a completely different activity pattern of genes, which, among other things, influence the host specificity of poxviruses—did the variola virus of the Viking era infect not only humans but also animals? The evolution of the poxvirus is clearly far more complex than previously assumed. Since the human poxvirus has followed such diverse genetic paths in the past, it is conceivable that the still-circulating animal poxviruses have evolved with similar diversity. One thing is certain: studying Viking skeletons gives us a better understanding of historical virus diversity. This, in turn, helps predict potential evolutionary paths and develop measures for monitoring and containment.
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[1] Barbara Mühlemann et al. Diverse variola virus (smallpox) strains were widespread in northern Europe in the Viking Age. Science 369, eaaw8977 (2020).
[2] https://www.dzif.de/de/schon-die-wikinger-hatten-pocken, 12.12.2024
[3] https://www.rki.de/DE/Content/InfAZ/A/Affenpocken/Ausbruch-2022-Situation-Deutschland.html, 12.12.2024
[4] https://flexikon.doccheck.com/de/Affenpockenvirus, 12.12.2024
[5] https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_Mpox_Affenpocken.
html?nn=16732866, 12.12.2024
[6] https://www.who.int/news/item/14-08-2024-who-director-general-declares-mpox-outbreak-a-public-health-emergency-of-international-concern, 12.12.2024
[7] https://commons.wikimedia.org/wiki/File:African_mpox_epidemic.svg, 12.12.2024
[8] https://www.aidshilfe.de/mpox-affenpocken, 12.12.2024
[9] https://commons.wikimedia.org/wiki/File:Monkeypox.jpg, 12.12.2024
[10] https://commons.wikimedia.org/wiki/File:Poxviridae_virion_image.svg, 12.12.2024
[11] Bidgood SR, Samolej J, Novy K, Collopy A, Albrecht D, Krause M, Burden JJ, Wollscheid B, Mercer J. Poxviruses package viral redox proteins in lateral bodies and modulate the host oxidative response. PLoS Pathog. 2022 Jul 14;18(7):e1010614.
[12] https://en.wikipedia.org/wiki/Monkeypox_virus, 12.12.2024
[13] Shchelkunov SN, Totmenin AV, Safronov PF, Mikheev MV, Gutorov VV, Ryazankina OI, Petrov NA, Babkin IV, Uvarova EA, Sandakhchiev LS, Sisler JR, Esposito JJ, Damon IK, Jahrling PB, Moss B. Analysis of the monkeypox virus genome. Virology. 2002 Jun 5;297(2):172-94.
[14] Isidro, J., Borges, V., Pinto, M. et al. Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus. Nat Med 28, 1569–1572 (2022).
Preview Image: https://commons.wikimedia.org/wiki/File:Colorized_transmission_electron_micrograph_of_monkeypox_virus_particles_(green).jpg
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