A comprehensive review of monkeypox virus and mpox characteristics

Abstract

Monkeypox virus (MPXV) is the etiological agent of monkeypox (mpox), a zoonotic disease. MPXV is endemic in the forested regions of West and Central Africa, but the virus has recently spread globally, causing outbreaks in multiple non-endemic countries. In this paper, we review the characteristics of the virus, including its ecology, genomics, infection biology, and evolution. We estimate by phylogenomic molecular clock that the B.1 lineage responsible for the 2022 mpox outbreaks has been in circulation since 2016. We interrogate the host-virus interactions that modulate the virus infection biology, signal transduction, pathogenesis, and host immune responses. We highlight the changing pathophysiology and epidemiology of MPXV and summarize recent advances in the prevention and treatment of mpox. In addition, this review identifies knowledge gaps with respect to the virus and the disease, suggests future research directions to address the knowledge gaps, and proposes a One Health approach as an effective strategy to prevent current and future epidemics of mpox.

Keywords: antivirals; biosafety; epidemiology; evolution; genomics; infection biology; monkeypox; one health.

Figure 1

Timeline of MPXV emergence and re-emergence in endemic regions and globally. Each event timeline indicates the pre-2022 outbreak in endemic and non-endemic countries and the 2022 mpox outbreak (Durski et al., 2018; World Health Organization, 2022). Note: Cameroon (CMR), the Central African Republic (CAR), Cote d’Ivoire (CIV), the Democratic Republic of the Congo (DRC), Gabon (GAB), the United Kingdom (GBR), Liberia (LBR), Nigeria (NGA), Israel (ISR), Sierra Leone (SLE), Singapore (SGP), the Republic of the Congo (COD), South Sudan (SSD), the United States of America (USA).

Figure 2

Timeline of MPXV re-emergence and global spread. (A) Global map of 2022 mpox of the geographical distribution of the outbreak as of December 5, 2022 (Durski et al., 2018; World Health Organization, 2022). The names of countries with at least one case pre-2022 are labelled. (B) Global maps zoom on Europe. (C) Weekly cumulative number of cases reported to World Health Organization (WHO) stacked by WHO region. The line/dot represents the cumulative number of countries affected. Countries: Cameroon (CMR), the Central African Republic (CAR), Cote d’Ivoire (CIV), the Democratic Republic of the Congo (DRC), Gabon (GAB), the United Kingdom (GBR), Liberia (LBR), Nigeria (NGA), Israel (ISR), Sierra Leone (SLE), Singapore (SGP), the Republic of the Congo (COD), South Sudan (SSD), the United States of America (USA).

Figure 3

Genome annotation, phylogenomic tree, maximum clade credibility tree, and mutation map of MPXV. (A) Schematic presentation of MPXV genome. Annotation is given for MPXV reference strain NC_063383.1. The orientation of ORFs is given by the direction of arrow heads. ORFs are named according to the nomenclature of orthopoxvirus genes (example: OPG001) (Senkevich et al., 2021) and VACV Western Reserve nomenclature (example: J1L). MPXV genome consists of a conserved central region (OPG048 to OPG151) flanked by variable terminal regions, which contain inverted terminal repeats (ITR) (Shchelkunov et al., 2001; Shen-Gunther et al., 2023). The central region encodes genes for genome replication, essential enzymes, and structural proteins. Conversely, the variable terminal regions contain mainly virulence and host-range genes (Shchelkunov et al., 2001). MPXV genome encompasses >190 nonoverlapping open reading frames (ORFs) (Shchelkunov et al., 2001; Hendrickson et al., 2010; Shen-Gunther et al., 2023) and at least 4 ORFs are located in ITR (Shchelkunov et al., 2002; Likos et al., 2005; Nakazawa et al., 2013). ORFs are colored based on their function. (B) Bayesian Inference phylogenetic tree of concatenated 62 non-recombinant conserved genes from 197 MPXV genomes retrieved from GenBank and GISAID. Recombination detection program 4 (RDP4) (Martin et al., 2015) was used to detect recombination in the 62 conserved genes (Diaz-Cánova et al., 2022a) and the phylogenetic tree was reconstructed using MrBayes v3.2.7 (Ronquist et al., 2012), as previously published (Diaz-Cánova et al., 2022a). Black squares at the nodes indicate posterior probabilities ≥ 0.95. The scale bar represents expected substitutions per site. (C) Time-Scaled Bayesian Inference phylogenetic tree of concatenated 62 non-recombinant conserved genes from 197 MPXV strains. The presence of a temporal signal within the dataset was examined by regression of genetic divergence (root-to-tip genetic distance) and the sampling date using TempEst v.1.5.3 (Rambaut et al., 2016). The Maximum likelihood tree of 62 non-recombinant conserved genes built as described previously (Diaz-Cánova et al., 2022a) was used for TempEst. The maximum-clade-credibility (MCC) tree was generated using BEAST 1.10.4 (Suchard et al., 2018), using a log-normal strict clock, constant population size, and HKY substitution model. Markov Chain Monte Carlo (MCMC) chains were run until reaching convergence. The convergence of MCMC chains was checked by the effective sample size (ESS) values >200 for each parameter (after burn-in) using Tracer v1.7.1 (Rambaut et al., 2018). The maximum-clade-credibility (MCC) tree was generated using TreeAnnotator v1.10.4. Black circles at the nodes indicate posterior probabilities ≥ 0.9. The scale bar represents expected substitutions per site. (D) Mutation map showing all 60 consensus substitutions. 51 of the 60 consensus nucleotide substitutions possessing APOBEC3 like pattern of mutation (GA > AA, GG > AG, and TC > TT). Twenty-eight of these were GA > AA substitutions, two were GG > AG (this mutational pattern is a product of APOBEC3G), twenty-one were TC > TT, and the remaining nine substitutions were not typical of APOBEC3 editing. (E) Synonymous and non-synonymous mutational count.

Figure 4

MPXV morphogenesis, signaling and immune evasion strategies. (A) The MPXV replication cycle. After attachment of the virion to the host cell membrane, the viral genome is released by uncoating followed by transcription and duplication of the viral genome. Translation and subsequent assembly results in IMV. MPXV virions can exist as intracellular mature virus (IMV), cell associated enveloped virus (CEV) and extracellular-enveloped virus (EEV). IMV assembles in the cytoplasm and consists of a core particle wrapped in a membrane. IMV particles egress from the infected cells by lysis, whereas some IMVs are transported through microtubules and wrapped by an intracellular membrane to produce an intracellular enveloped virus (IEV), which can further fuse with the cell membrane and be released to form EEV (Schmidt and Mercer, 2012; Sivan et al., 2016; Realegeno et al., 2020). Some EEVs remain attached to the cell surface (CEV) and are responsible for cell-to-cell spread, whereas EEV that detaches from the infected cells play a role in long-range dissemination within the host (Blasco and Moss, 1992). IMV particles are thought to be the form responsible for inter-host viral transmission. In contrast, EEV are known to be important for intra-host viral dissemination (Payne, 1980). (B) MPXV strategies to activate signaling pathways. Left panel: The canonical NFκB pathway requires activation of the cytoplasmic p65/p50 dimer, which is anchored into the cytoplasm through its interaction with IKα. The trimer IKKα/IKKβ/IKKγ will upon activation phosphorylate IKα, which is subsequently ubiquitinated and probed for proteasomal degradation. This results in release of p65/p50, which translocate to the nucleus and can induce transcription of NFκB target genes. Several MPXV proteins can perturb the NFκB pathway. Right panel: The JAK/STAT pathway consist of the tyrosine kinases JAK that phosphorylate and activate the transcription factor STAT. The MPXV proteins encoded by the genes H1L and D11L can inhibit activation of the JAK/STAT pathway. (C) MPXV avoids detection of virus-infection cells by cytotoxic CD8+T cells. Infected host cells will present viral peptide fragments by MHC-I molecules. These will be recognized by T cell receptors (TCR). Co-recognition of NKG2D ligand on the MPXV-infected cell and the NKG2D receptor on the CD8+ T cell is required. MPXV will prevent the latter interaction by expressing soluble NKG2D. Moreover, the cytokine gradient produced upon MPXV infection will be disturbed by MPXV-encoded proteins that will bind these cytokines such as TNFα, IL-1β.

Figure 5

Demographic characteristics and transmission routes of human mpox. Demographic characteristics of 2022 human mpox cases according to sex and age in three WHO regions based on data from 4727328. (A) African region, (B) European region and (C) region of Americas. The pyramid plots show the number of cases and percentage of overall cases. (D)Transmission of mpox in endemic and non-endemic regions pre-2022 and 2022 outbreak. The characteristics of outbreaks in the different regions were highlighted. Prior to 2022, mpox was limited to the endemic regions and cases outside the region were usually travel related. However, the 2022 outbreak in non-endemic region was not travel related and has been reported in several countries.