In a recent study posted to the bioRxiv* preprint server, researchers from Nigeria and the United Kingdom (UK) analyzed mpox virus genomes and found that divergent lineages of the mpox virus exhibiting human-to-human transmission existed in the Nigerian population before the 2022 spread of the virus outside of the endemic regions .
Mpox is a zoonotic infection caused by the mpox virus (MPXV), which belongs to the orthopox virus genus, similar to the smallpox-causing Variola viruses, Although largely endemic to West and Central Africa, the recent spread of MPXV to North America and Europe caused a global outbreak and indicated an increase in its human-to-human transmissibility, especially among men who have sex with men. This suggested that the virus had evolved a non-zoonotic method of transmission among humans, without requiring reintroduction into animal hosts.
Genetic studies have identified two major clades of mpox viruses—the Central African or Congo basin clade which is now called Clade I, and the West African clade called Clade II. While some phylogenetic studies have identified the lineage B.1, which caused the 2022 global outbreak, to be linked to the Clade II lineage that caused an outbreak in Nigeria in 2017, the lack of extensive genomic information made tracing the evolutionary origins of the B. .1 lineage difficult.
About the study
In the present study, the researchers analyzed 18 MPXV genomes acquired from mpox patients in Nigeria between 2019 and 2020. When genomes from the 2022 global mpox outbreak were compared to the reference genome MT903345, they were observed to share 47 single nucleotide mutations, of which 45 were associated with the cytidine deaminase activity of apolipoprotein B messenger ribonucleic acid-editing enzyme, catalytic polypeptide 3 (APOBEC3).
The 18 genomes used in this study were compared to the same reference genome MT903345 to identify single nucleotide polymorphisms (SNP) that could indicate increased human-to-human transmissibility. Furthermore, the concatenated amino acid sequences from the genome were examined independently for a more detailed analysis of the viral evolution.
The results indicated that the phylogenetic origin of the 18 sequences was in Clade IIb, and they were found to cluster within lineage A. A total of 149 SNPs were identified in these sequences, and 17 genomes were found to share 35 of these 149 SNPs. These SNPs are spread across the genome in characterized and uncharacterized genes, with some of these mutations causing alterations in amino acid sequences of proteins such as membrane protein and deoxyribonucleic acid (DNA) polymerase.
The frequency of mutations in the APOBEC3-like motifs among the 18 genome sequences was lower than that in the B.1 lineage from the 2022 outbreak sequences. The OP612686 and OP612687 genomes, which are phylogenetically closest to the 2022 outbreak lineage B.1 also share more of the APOBEC3 motif mutations with the B.1 lineage genomes. This indicated an association between non-zoonotic transmissibility and APOBEC3 motif mutations. It also suggested that MPXV circulating among the Nigerian population could contain divergent subpopulations, with demographic factors and differences in modes of transmission driving the divergence. In comparison, the higher frequency of APOBEC3 motif mutations in the B.1 lineage indicates a higher rate of mutation accumulation, possibly due to the rapid transmission through primary rashes.
The authors discussed the findings from another study which showed that three cases in the United States (US), concurrent with the global 2022 outbreak, but involving individuals that traveled from Africa were classified as Lineage A.2 and formed a separate cluster in the phylogenetic trees. This suggested that this lineage was present in Nigeria before the global outbreak of the B.1 lineage. To further support that inference, three of the sequences from the present study were found to be closely related to the A.2 lineage, and given the fact that these sequences were from samples obtained between 2019 and 2020, the A.2 lineage seems to have originated in West Africa.
Furthermore, analysis of the SNPs in the six A.2 lineages (three from the present study and three sequences from patients in the US) revealed that two of the Nigerian A.2 lineages were not direct ancestors of the USA2 sequences and that the A. .2 lineage was undergoing diversification. The A.2 lineage sequences also formed a long branch in the amino acid-based phylogeny, which distinctly separated them from the other lineage A viruses in Clade IIb.
The amino-acid-based phylogenetic analysis also revealed two other diverging clusters among the sequences from the present study and isolates from 2018 from the UK, Nigeria, and Israel, which cumulatively indicated the presence of multiple MPXV lineages with non-zoonotic transmissibility, in contrast to the earlier hypothesis of a single zoonotic transmission event and subsequent divergence.
To summarize, the results suggested that the MPXV lineage A.2, which was detected in the US concurrent with the 2022 outbreak of the B.1 lineage, originated in West Africa and was present in the Nigerian population before it spread to North America. Furthermore, contrary to the earlier hypotheses that the non-endemic lineages are a result of a single zoonotic event and subsequent divergence and human-to-human transmission, the results suggest that multiple lineages with non-zoonotic transmissibility were already in circulation in Nigeria.
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