Genomic and ultrastructural analysis of monkeypox virus in skin lesions and in human/animal infected cells reveals further morphofunctional insights into viral pathogenicity.

Monkeypox (MPOX) is a zoonotic disease that affects humans and other primates, resulting in a smallpox-like illness. It is caused by monkeypox virus (MPXV), which belongs to the Poxviridae family. Clinically manifested by a range of cutaneous and systemic findings, as well as variable disease severity phenotypes based on the genetic makeup of the virus, the cutaneous niche and respiratory mucosa are the epicenters of MPXV pathogenicity. Herein, we describe the ultrastructural features of MPXV infection in both human cultured cells and cutaneous clinical specimens collected during the 2022-2023 MPOX outbreak in New York City that were revealed through electron microscopy. We observed typical enveloped virions with brick-shaped morphologies that contained surface protrusions, consistent with the classic ultrastructural features of MPXV. In addition, we describe morpho-functional evidence that point to roles of distinct cellular organelles in viral assembly during clinical MPXV infection. Interestingly, in skin lesions, we found abundant melanosomes near viral assembly sites, particularly in the vicinity of mature virions, which provides further insight into virus-host interactions at the subcellular level that contribute to MPXV pathogenesis. These findings not only highlight the importance of electron microscopic studies for further investigation of this emerging pathogen but also in characterizing MPXV pathogenesis during human infection.

Monkeypox virus (MPXV) genomics: A mutational and phylogenomic analyses of B.1 lineages.

The recent increase in monkeypox (MPX) cases has attracted attention of public health authorities due to its quick spread and transmission across non-endemic regions. This outbreak, unlike previous ones, displays different epidemiological features and transmission dynamics, which appear to be largely influenced by the newly divergent MPX lineages (B.1). Yet, the genomic characteristics driving the high dispersal and diversification of these lineages remain largely unknown. Herein, we sought to explore and characterize the genomic features and phylogenetic diversity of the B.1 lineages through a comparative genomic analysis inclusive of 1900 high quality complete MPXV genomes. Our analyses indicate that the current MPXV-2022 outbreak encompasses thirteen derived lineages with ten unique non-synonymous mutations in several genes linked to immune evasion, virulence factors and host recognition. Such mutations may translate in the rapid evolution and diversification of current MPXV lineages. Moreover, our analyses uncovered signals of genomic modifications suggestive of immune-modulatory enzymatic activity, such as APOBEC3 editing, which, as previously suggested could have favored evolutionary trends leading to the rapid spread of MPXV into non-endemic countries. Genomic surveillance continues to play a major role in unveiling the genomic signatures signaling potential adaptation of this emerging MPXV lineage and how it will continue to impact public health in the near future.