A recent International Journal of Molecular Sciences review summarizes available knowledge on the monkeypox virus, including its pathogenicity, risk to the human population, and methods that will help limit its spread.

Study: Monkeypox: A Latest 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 primary human monkeypox infection was reported within 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 primary monkeypox infection patient experienced secondary infections and eventually died within the hospital. Several additional cases of monkeypox infection were identified over the following decade, mostly amongst children within the Democratic Republic of the Congo, in addition to other Western and Central African countries.

Through the Nineteen Seventies and 80s, the case fatality rate (CFR) as a result of monkeypox infection was roughly 11% in DRC. The very best CFR was reported amongst children who were below 4 years of age.

Outside of Africa, the primary monkeypox outbreak was reported in the US in 2003 as a result of an exotic pet import from Ghana. Moreover, several small clusters and single cases were reported in the UK, Singapore, Israel, and the U.S. lately, all of which were related to previous travel to Nigeria.

The present monkeypox outbreak

On May 4, 2022, a patient with an unexplained rash and up to date travel history to Nigeria was admitted to a hospital within the U.K. The diagnosis of monkeypox infection was confirmed by polymerase chain response (PCR) assay using a vesicular swab.

Thereafter, hundreds of recent monkeypox cases have been reported in over 50 countries on six continents. This has been the most important 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 present outbreak, has been more commonly diagnosed amongst men who’ve sex with men (MSM) or those with multiple sexual partners.

The World Health Organization (WHO) has increased the worldwide public health risk for monkeypox infection from low to moderate. Particularly, the chance level has been increased to high within the European Regions, which comprises over 80% of recent monkeypox infections.

Countries with confirmed (red) or suspected (pink) MPX cases through 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 [8]. The bottom 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 can be 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’ve not been found to evolve from one another.

Monkeypox strains could 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 accountable for the primary human outbreak, while the WA clade is less pathogenic and accountable for the 2022 outbreak, in addition to other smaller outbreaks.

Two distinct virus lineages have been identified from the present outbreak and are known 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.

Animal reservoirs

The primary animal reservoir of monkeypox has not been confirmed, because the virus has been detected in multiple species reminiscent of African squirrels, wild rodents, prairie dogs, sooty mangabey monkeys,Zambian baboons, Colobus monkeys, and chimpanzees. Together with wild animal contact, consumption of bushmeat may increase the chance of monkeypox infection.

Genome and morphology

The monkeypox genome is about 197,000 base pairs in size, which incorporates greater than 190 non-overlapping open reading frames (ORFs) in addition to hairpin termini. Roughly 90 ORFS are essential for the replication and morphogenesis of the monkeypox virus.

Other non-essential ORFs assist in immunomodulation, host tropism, and pathogenesis. The monkeypox virions are either barrel or oval-shaped, with a dumbbell-shaped nucleoprotein core that incorporates double-stranded DNA.

The virion consists of over 30 membrane and structural proteins, transcriptional enzymes, in addition to DNA-dependent ribonucleic acid (RNA) polymerases which can be encoded by the virus.

The monkeypox virus has two mature forms known as intracellular mature virus (IMV) and extracellular enveloped virus (EEV).

Replication and transmission cycle

Handling of infected rodents is a standard 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 may 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 situated on the surface of the goal cell. Thereafter, the virus enters the host cell by direct fusion or endosomal pathway and releases the viral core into the cytoplasm.

That is followed by viral transcription and translation of the early, intermediate, and late proteins. The DNA synthesis for poxviruses takes place in cytoplasmic structures that are also referred to as “factories.”

Most mature virions remain contained in the cell, while few are transported through microtubules and grow to be enveloped. These enveloped virions either propel themselves towards an adjoining cell or exit the host cell through fusion with the cytoplasmic membrane.

Immune evasion of monkeypox virus

Multiple mechanisms are utilized by the poxvirus to evade the host immune system. The monkeypox virus doesn’t appear to induce the expression of the interferon-stimulated gene (ISG); nevertheless, 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 stopping 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, reminiscent of 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 just isn’t reported within the WA clade, which may be suggestive of a lower CFR. Moreover, removal of the CCP gene from the CB clade has been related to reduced disease mortality and morbidity.

Mutation and adaptation

The monkeypox virus mutates less incessantly as a result of greater stability of the double-stranded DNA, together with DNA polymerase mediated 3’-5’ proofreading exonuclease activity. Evaluation of nucleotide components has indicated that the monkeypox viral genome consists of two times greater AT content as in comparison with GC content. Mammalian editing enzymes have been reported to introduce a bias within the usage of genomic nucleotides through selective pressure on the viral genome.

Furthermore, recombination may induce the gain or lack of genes for poxviruses. Nevertheless, the impact of unique mutations within the strains resulting in the 2022 outbreak remains to be not known.

Clinical features and pathogenesis

Essentially 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. Nevertheless, many patients have reported atypical disease symptoms that include no or few lesions localized within the perineal or genital area, anal bleeding, and pain.

Symptoms typically appear between five and 21 days until resolving on their very own between two and 4 weeks after the initial infection. Nevertheless, young children and immunosuppressed patients have been reported to experience severe disease that requires hospitalization, with monkeypox infection while pregnant often related to fetal death.

Other complications of monkeypox infection include encephalitis, sepsis, bronchopneumonia, and lack of vision. The CFRs for the CB clade were reported to be as much as 10% and three.6% for the WA clade in prior African outbreaks.

Vaccination against monkeypox virus

Smallpox vaccination is a standard measure used to regulate monkeypox virus transmission. The truth is, previous research has indicated that the viral attack rate was significantly lower in vaccinated individuals as in comparison with unvaccinated individuals.

Two vaccines which have been approved within the U.S. and Europe for human use include Aventis Pasteur Smallpox Vaccine (APSV) and Single-dose ACAM2000. Nevertheless, these vaccines contain replication-competent viruses and can’t be administered to immunocompromised individuals.

Recently, a two-dose Modified Vaccinia Ankara virus Bavarian Nordic (MVA-BN) vaccine has been approved. This vaccine incorporates a replication-deficient virus and, consequently, is protected for immunocompromised individuals. Moreover, an attenuated smallpox vaccine referred to as LC16m8 has been developed in Japan and is taken into account effective against monkeypox infections.

Treatment 

Previous studies have reported that the usage of vaccinia immune globulin intravenous (VIGIV) is protected and effective in patients with monkeypox infection. Tecovirimat is the one European Medicines Agency (EMA)- and U.S. Food and Drug Administration (FDA)-approved drug that’s used for the treatment of severe monkeypox patients.

Cidofovir is taken into account to be effective against severe monkeypox infection in macaques; nevertheless, its efficacy in humans has not yet been determined.

Conclusions

The present 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 may be a high risk of the monkeypox virus establishing an animal reservoir in non-endemic regions as a result of its high species tropism. Subsequently, increasing safety measures, vaccination, antiviral drugs, and monkeypox surveillance is vital to regulate the specter of MPX.

Journal reference:

• Kmiec, D. & Kirchhoff, F. (2022). Monkeypox: A Latest Threat? International Journal of Molecular Sciences. doi:10.3390/ijms23147866.