A recent International Journal of Molecular Sciences review summarizes available knowledge on the monkeypox virus, including its pathogenicity, risk to the human population, and strategies that can help limit its spread.
Study: Monkeypox: A New Threat? Image Credit: Kateryna Kon / Shutterstock.com
History of monkeypox infection
The monkeypox virus is a pox-like disease that was first identified in macaque monkeys at a research facility in Denmark in 1958. Subsequently, the first human monkeypox infection was reported in the Democratic Republic of the Congo (DRC) in 1970 in a nine-month-old patient who experienced fever and a pox-like rash that led to hemorrhagic lesions, which healed in two weeks.
Despite the resolution of the initial infection, the first monkeypox infection patient experienced secondary infections and eventually died in the hospital. Several additional cases of monkeypox infection were identified over the next decade, mostly among children in the Democratic Republic of the Congo, as well as other Western and Central African countries.
During the 1970s and 80s, the case fatality rate (CFR) due to monkeypox infection was approximately 11% in DRC. The highest CFR was reported among children who were below four years of age.
Outside of Africa, the first monkeypox outbreak was reported in the United States in 2003 due to an exotic pet import from Ghana. Additionally, several small clusters and single cases were reported in the United Kingdom, Singapore, Israel, and the U.S. in recent years, all of which were associated with previous travel to Nigeria.
The current monkeypox outbreak
On May 4, 2022, a patient with an unexplained rash and recent travel history to Nigeria was admitted to a hospital in the U.K. The diagnosis of monkeypox infection was confirmed by polymerase chain reaction (PCR) assay using a vesicular swab.
Thereafter, thousands of new monkeypox cases have been reported in over 50 countries on six continents. This has been the largest non-endemic outbreak of the monkeypox virus with no link between infected people or travel to endemic regions.
The monkeypox virus primarily spreads through close physical contact and, in the current outbreak, has been more commonly diagnosed among men who have sex with men (MSM) or those with multiple sexual partners.
The World Health Organization (WHO) has increased the global public health risk for monkeypox infection from low to moderate. In particular, the risk level has been increased to high in the European Regions, which comprises over 80% of new monkeypox infections.
Countries with confirmed (red) or suspected (pink) MPX cases during the 2022 non-endemic outbreak. Regions, where MPX was endemic prior to 2022, are shown in black. The map includes cases reported until 12 July 2022 . The base layer map was obtained from https://commons.wikimedia.org/wiki/File:BlankMap-World.svg (accessed on 1 July 2022).
Classification and phylogeny
The monkeypox virus belongs to the Orthopox genus of the Poxviridae family. This is a double-stranded DNA virus, with its closest relatives including vaccinia (VACV) and variola (VARV) viruses. Although VARV and monkeypox share 96% sequence similarity, they have not been found to evolve from each other.
Monkeypox strains can be classified into two separate clades, including the West African (WA) and Congo Basin (CB) clades. The CB clade is reported to be more pathogenic and was responsible for the first human outbreak, while the WA clade is less pathogenic and responsible for the 2022 outbreak, as well as other smaller outbreaks.
Two distinct virus lineages have been identified from the current outbreak and are referred to as B.1 and A.2. B.1 emerged from a single individual who traveled from Nigeria to Maryland in 2021, while A.2 is believed to have had an independent introduction.
The main animal reservoir of monkeypox has not been confirmed, as the virus has been detected in multiple species such as African squirrels, wild rodents, prairie dogs, sooty mangabey monkeys,Zambian baboons, Colobus monkeys, and chimpanzees. Along with wild animal contact, consumption of bushmeat can also increase the risk of monkeypox infection.
Genome and morphology
The monkeypox genome is about 197,000 base pairs in size, which includes more than 190 non-overlapping open reading frames (ORFs) as well as hairpin termini. Approximately 90 ORFS are important for the replication and morphogenesis of the monkeypox virus.
Other non-essential ORFs help in immunomodulation, host tropism, and pathogenesis. The monkeypox virions are either barrel or oval-shaped, with a dumbbell-shaped nucleoprotein core that contains double-stranded DNA.
The virion consists of over 30 membrane and structural proteins, transcriptional enzymes, as well as DNA-dependent ribonucleic acid (RNA) polymerases that are encoded by the virus.
The monkeypox virus has two mature forms referred to as intracellular mature virus (IMV) and extracellular enveloped virus (EEV).
Replication and transmission cycle
Handling of infected rodents is a common source of zoonotic monkeypox transmission, while human-to-human spread typically occurs from contact with lesions, respiratory droplets, body fluids, and contaminated objects. Previous studies with macaques have indicated that the virus first infects the lower airway epithelial cells and can subsequently spread to the lymph nodes, spleen, thymus, skin, gastrointestinal tract, oral mucosa, and reproductive system.
The initial attachment of the monkeypox virion arises through the interaction of external virion proteins with cellular glycosaminoglycans located on the surface of the target cell. Thereafter, the virus enters the host cell by direct fusion or endosomal pathway and releases the viral core into the cytoplasm.
This is followed by viral transcription and translation of the early, intermediate, and late proteins. The DNA synthesis for poxviruses takes place in cytoplasmic structures which are also known as “factories.”
Most mature virions remain inside the cell, while few are transported through microtubules and become enveloped. These enveloped virions either propel themselves towards an adjacent cell or exit the host cell through fusion with the cytoplasmic membrane.
Immune evasion of monkeypox virus
Multiple mechanisms are used by the poxvirus to evade the host immune system. The monkeypox virus does not appear to induce the expression of the interferon-stimulated gene (ISG); however, it does suppress the expression of interleukin 1 alpha (IL-1α), IL-1β, tumor necrosis factor-alpha (TNF-α), IL-6, and C-C motif chemokine ligand 5 (CCL5).
This virus also suppresses the antiviral response by preventing the phosphorylation of pattern recognition immune receptor protein kinase R (PKR) and eukaryotic initiation factor 2 alpha (eIF2α).
The monkeypox viral genome encodes several proteins that aid in immune evasion, such as B16, which inhibits the signaling of type I interferon (FN), a homolog of D7L that inhibits IL-18, zinc-finger antiviral protein (ZAP), which selectively pressurizes CpGs in viral genomes, and complement control protein (CCP), which prevents initiation of the complement activation pathway.
The CCP gene is not reported in the WA clade, which might be suggestive of a lower CFR. Additionally, removal of the CCP gene from the CB clade has been associated with reduced disease mortality and morbidity.
Mutation and adaptation
The monkeypox virus mutates less frequently due to greater stability of the double-stranded DNA, along with DNA polymerase mediated 3’-5’ proofreading exonuclease activity. Analysis of nucleotide components has indicated that the monkeypox viral genome consists of two times greater AT content as compared to GC content. Mammalian editing enzymes have been reported to introduce a bias in the usage of genomic nucleotides through selective pressure on the viral genome.
Moreover, recombination can also induce the gain or loss of genes for poxviruses. However, the impact of unique mutations in the strains leading to the 2022 outbreak is still not known.
Clinical features and pathogenesis
The most common symptoms of monkeypox infection include fever, body ache, malaise, sore throat, enlarged lymph nodes, fatigue, and a body rash that ultimately crusts over and heals. However, many patients have reported atypical disease symptoms that include no or few lesions localized in the perineal or genital area, anal bleeding, and pain.
Symptoms typically appear between five and 21 days until resolving on their own between two and four weeks after the initial infection. However, young children and immunosuppressed patients have been reported to experience severe disease that requires hospitalization, with monkeypox infection during pregnancy often associated with fetal death.
Other complications of monkeypox infection include encephalitis, sepsis, bronchopneumonia, and loss of vision. The CFRs for the CB clade were reported to be up to 10% and 3.6% for the WA clade in prior African outbreaks.
Vaccination against monkeypox virus
Smallpox vaccination is a common measure used to control monkeypox virus transmission. In fact, previous research has indicated that the viral attack rate was significantly lower in vaccinated individuals as compared to unvaccinated individuals.
Two vaccines that have been approved in the U.S. and Europe for human use include Aventis Pasteur Smallpox Vaccine (APSV) and Single-dose ACAM2000. However, these vaccines contain replication-competent viruses and cannot be administered to immunocompromised individuals.
Recently, a two-dose Modified Vaccinia Ankara virus Bavarian Nordic (MVA-BN) vaccine has been approved. This vaccine contains a replication-deficient virus and, as a result, is safe for immunocompromised individuals. Additionally, an attenuated smallpox vaccine known as LC16m8 has been developed in Japan and is considered effective against monkeypox infections.
Previous studies have reported that the use of vaccinia immune globulin intravenous (VIGIV) is safe and effective in patients with monkeypox infection. Tecovirimat is the only European Medicines Agency (EMA)- and U.S. Food and Drug Administration (FDA)-approved drug that is used for the treatment of severe monkeypox patients.
Cidofovir is considered to be effective against severe monkeypox infection in macaques; however, its efficacy in humans has not yet been determined.
The current review demonstrates that transmission of the monkeypox virus takes place only through close physical contact. The monkeypox virus most severely affects children, immunocompromised individuals, and pregnant women.
There is a high risk of the monkeypox virus establishing an animal reservoir in non-endemic regions due to its high species tropism. Therefore, increasing safety measures, vaccination, antiviral drugs, and monkeypox surveillance is important to control the threat of MPX.
- Kmiec, D. & Kirchhoff, F. (2022). Monkeypox: A New Threat? International Journal of Molecular Sciences. doi:10.3390/ijms23147866.