Monkeypox virus: The changing facets of a zoonotic pathogen

Abstract

In the last five years, the prevalence of monkeypox has been increasing both in the regions considered endemic for the disease (West and Central Africa) and worldwide. Indeed, in July 2022, the World Health Organization declared the ongoing global outbreak of monkeypox a public health emergency of international concern. The disease is caused by monkeypox virus (MPXV), a member of the Orthopoxvirus genus, which also includes variola virus (the causative agent of smallpox) and vaccinia virus (used in the smallpox eradication campaign). Here, we review aspects of MPXV genetic diversity and epidemiology, with an emphasis on its genome structure, host range, and relationship with other orthopoxviruses. We also summarize the most recent findings deriving from the sequencing of outbreak MPXV genomes, and we discuss the apparent changing of MPXV evolutionary trajectory, which is characterized by the accumulation of point mutations rather than by gene gains/losses. Whereas the availability of a vaccine, the relatively mild presentation of the disease, and its relatively low transmissibility speak in favor of an efficient control of the global outbreak, the wide host range of MPXV raises concerns about the possible establishment of novel reservoirs. We also call for the deployment of field surveys and genomic surveillance programs to identify and control the MPXV reservoirs in West and Central Africa.

Keywords: Genetic diversity; Genome features; Geographic structure; Monkeypox; Zoonotic transmission.

Fig. 1

Orthopoxvirus genetic diversity. (A) Phylogenetic tree of 12 recognized orthopoxvirus species (Akhmeta virus, AKMV; camelpox virus, CMLV; cowpox virus, CPXV; ectromelia virus, ECTV; MPXV; orthopoxvirus Abatino, OPVA; raccoonpox virus, RPXV; skunkpox virus, SPXV; taterapox virus, GBLV, also known as TATV; VACV; VARV; volepox virus, VPXV) plus Alaska virus (AKPV). The tree is mid-point rooted and was constructed with IQTREE (Trifinopoulos et al., 2016), using a concatenated alignment of 49 genes shared by all poxviruses (Upton et al., 2003). Black dots indicate internal nodes with bootstrap support >0.8. Animal silhouettes were obtained from the Phylopic website (http://www.phylopic.org/) and are representative of the host ranges of different viruses (Silva et al., 2020). (B) Whole-genome alignment of MPXV, VARV, VACV, CPXV, and ECTV obtained with progressive Mauve (v.2.3.1) (Darling et al., 2004,Darling et al., 2010). Each genome is laid out in a horizontal track, with annotated coding regions denoted as boxes. Vertical red bars represent genome boundaries. A similarity plot generated by progressive Mauve is shown above each genome, with colors indicating regions that align to part of any another genome and thus represent locally collinear blocks. A similarity profile is also plotted within blocks, with height proportional to the level of conservation in that region. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Structure of the MPXV genome. A schematic representation of the MPXV genome is reported based on NCBI annotation and gene positions of the reference strain (NC_003310, clade I). Arrowheads indicate gene orientation. Genes are colored based on the function/category they belong to (see legends for details). Forty-nine genes shared among all poxviruses are shown in bold and asterisks denote genes that are deleted/truncated in clade IIa/IIb genomes (see also Table 1). Vertical triangles indicate nonsynonymous single nucleotide variants that are fixed (blue) or polymorphic (red) in B.1 genomes. ITR: inverted terminal repeats. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

MPXV phylogenetic relationships in the endemic regions. A phylogenetic tree of 89 MPXV genomes from the endemic regions was generated using IQTREE (Trifinopoulos et al., 2016) and virus sampling location was placed on a geographic map using country (indicated by colors) or, when possible, sub-region information. Identical genomes were excluded. The most internal nodes with bootstrap support >0.8 are denoted with dots. The gray color denotes exported human cases (before 2021) with country of destination shown at the end of the dashed lines. The route of exposure and the total number of cases (index and secondary) are reported (Simpson et al., 2020,Reynolds et al., 2006,Mauldin et al., 2022,Ng et al., 2019). Clades are labeled based on to the nomenclature proposed by Happi (Happi et al., 2022). DRC: Democratic Republic of the Congo; CAR: Central African Republic.

Fig. 4

Global MPXV phylogenetic distribution. Phylogenetic tree of 79 representative MPXV/hMPXV1 strains sampled worldwide. A conserved genomic region (Kugelman et al., 2014) was aligned using MAFFT and the tree was generated using IQTREE (Trifinopoulos et al., 2016). Clades are labeled based on the nomenclature proposed by Happi and colleagues (Happi et al., 2022). Black dots indicate internal nodes with bootstrap support >0.8, blue dots indicate clade IIb strains sampled before 2021. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)