Perspective delves into the rising threat of the MPX virus

In a perspective published in the journal Nature Microbiology, Bernard Moss of the Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases collates and discusses available scientific knowledge on the MPX virus, the cause of the zoonotic disease pox (formerly “monkeypox”). Given its sudden and alarming global surge in prevalence (38 reported cases between 1970-1979 to over 91,000 cases between 2022-2023) and the first reported documentation of sexual transmission (mainly in men who have sex with men [MSM]), the disease has now been included in the World Health Organization’s (WHO’s) External Situation Report #30, highlighting the need for a better understanding of the virus to tackle novel incidences.

The present review discusses the biology and genetics of MPXV, its epidemiology, potential animal reservoirs, functional genetics, and the potential for using animal models in research to curb the disease’s spread. It highlights the dearth of current scientific knowledge in the field and the need for additional research to elucidate the mechanisms of the disease’s human interactions, focusing on interpreting the modes of action of MPXV’s three known clades (1, 2a, and 2b).

Perspective: Understanding the biology of monkeypox virus to prevent future outbreaks. Image Credit: Dotted Yeti / Shutterstock

What is MPXV, and why are clinicians concerned about its disease?

The monkeypox virus (MPXV) is a zoonotic disease-causing member of the poxvirus family belonging to the Orthopoxvirus genus (subfamily Chordopoxvirinae). It is closely related to the variola virus (VARV, the agent of smallpox), the cowpox virus (CPXV), and the ectromelia virus (ECTV, the agent of the rodent disease mousepox). MPXV was first isolated and described from captive cynomolgus monkeys in 1958, with human infections identified from Central and West Africa in the early 1970s.

While not as clinically dangerous as the now-eradicated smallpox disease, pox is known to share the former’s symptoms of pox-like skin lesions, high fevers, vesicular-pustular eruptions, and lymphadenopathy. Mortality rates from the disease are reported to vary from <3.6% (West Africa) to ~10.6% (Central Africa). Alarmingly, reported cases of mpox have increased exponentially, from only 38 reported cases between 1970-79 to more than 91,000 cases between 2022-23. Formerly restricted to Central and West Africa, the disease has now been identified in the United Kingdom (UK), Israel, the United States of America (US), Singapore, and (as of November 2023) 111 more countries globally.

The surge in global prevalence, the discovery of human-to-human transmission, and the rise in global mortality (167 confirmed deaths between 2022-23) have prompted the World Health Organization (WHO) to label MPXV a “public health emergency of international concern” and include it in the former’s External Situation Report #30. Unfortunately, despite a prolonged history of the disease, research into MPXV remains scant. The present review aims to synthesize, collate, and discuss available scientific literature on the epidemiology of MPXV’s three known clades (1, 2a, and 2b) to equip clinicians and policymakers with the information required to curb the disease’s spread and potentially eradicate it in a fashion similar to the eradication of smallpox.

Biology, genetics, and functional genetics of MPXV

Like all other poxviruses, MPXV is a large double-stranded DNA virus that hijacks its (usually mammalian) host’s cell cytoplasm for survival and replication. Given the dearth of MPXV-specific research, most of our understanding of MPXV biology is derived from observations of the biology, epidemiology, and functional genetics of the VACV. In brief, the virus first binds to the host cell, fuses with the cellular membranes, and then releases its core into the cell’s cytoplasm. This release triggers the transcription of viral messenger RNAs (mRNAs), which encode 1. Enzymes for viral genome replication, 2. Intermediate-stage transcription RNAs, and 3. Surface proteins for host immune evasion and defense.

“The rate of viral evolution is determined mostly by the frequency of mutations. The poxvirus-encoded proofreading DNA polymerase has a low error rate, and analyses of VARV in humans and MPXV in chimpanzees indicate 1 × 10−5 and 2 × 10−6 nucleotide substitutions per site per year, respectively. This rate is considerably lower than the 0.8–2.38 × 10–3 and 2 × 10−3 nucleotide substitutions per site per year estimated for SARS-CoV-223 and influenza virus24, respectively. In vitro studies suggest that transient gene duplications (known as the accordion model) may precede further orthopoxviral mutational events, allowing accelerated adaptation to host antiviral defenses.”

Recent genetic research has revealed that the hitherto assumed single MPXV strain is, in fact, composed of three clades – Clade 1 is found predominantly in Central African countries, and Clades 2a and 2b are found mainly in Western Africa. The genomic difference between the clades ranges from 4-5% (clade 1 versus clades 2a/2b) and ~2% between clades 2a and 2b.

“Most clade differences are non-synonymous nucleotide polymorphisms and could potentially affect replication or host interactions. However, nearly all genes in clades I, IIa and IIb seem to be intact, as exemplified by the conserved lengths of the host interactions genes.”

While functional genetics studies have identified the role of deletions in substantially reducing viral replication in non-human-primate (NHP) models, this research remains in its infancy, and further research is required before genetic interventions can be used to fight the war on MPXV.

Epidemiology and animal reservoirs

Before the recent global outbreaks of 2018-19 and 2022-23, mpox cases were mainly restricted to Central and West Africa. However, given civil unrest in the region, lack of medical testing facilities in remote rural villages, and misidentification of mpox as smallpox before the latter’s eradication, mpox prevalence estimates are assumed to be underestimations.

“Case reporting, which is required in the DRC but without verification, has indicated an upward trend of cases49 from 38 in 1970–1979 to 18,788 in 2010–2019 and 6,216 in 2020. A further 12,569 cases were reported between 1 January and 12 November 2023. Lower numbers have been reported in other Central African countries, including the Central African Republic, Cameroon, Congo, Gabon and South Sudan, where reporting is not mandatory. Primary zoonotic infection is thought to occur by hunting, handling or consumption of wild animals in tropical rainforests.”

Animal reservoirs are considered the most frequent transmission routes for mpox, with men having sex with men (MSM) following the former in prevalence. Despite captive Asian monkeys being the source of the first identified MPXV, studies on their wild counterparts have failed to identify infected wild populations in Asia. In contrast, the lowlands of Central and West Africa have revealed vast populations of rodents (usually arboreal), monkeys, and bats infected with the disease. The highest prevalence has been found in rodents belonging to the Funisciuris and Heliosciuris genera, considered the disease’s main zoonotic reservoirs.

Conclusions

Despite several decades following mpox’s discovery, our knowledge about the disease and its viral mechanisms remains severely lacking. Future research elucidating the biology of MPXV, especially its modes of host immune evasion and interactions, would help curb its transmission, especially in Africa.

“A more equitable distribution of vaccines and therapeutics, a greater understanding of mpox epidemiology, identification of MPXV animal reservoirs that can transmit MPXV to humans, and a better understanding of human-to-human transmission are all needed if we are to better manage or indeed prevent future mpox outbreaks.”

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