Abstract
The recent outbreak of Monkeypox displays novel transmission features. The circulating strain is a descendant of a lineage that had been circulating in Nigeria since 2017. The prognosis of monkeypox disease (MPX) with the circulating strain is generally good but the estimated primary reproduction number (R0) among men who have sex with men (MSM) was above 1 suggesting efficient person-to-person transmission. Different mechanisms of viral entry and egress, as well as virus-coded host factors, are the main biological determinants of poxvirus transmissibility. OPXV evolution is driven by gene loss of virus-host interacting genes and selective pressure from host species using unique adaptive strategies at the gene and nucleotide level. In this context, we evaluated the effects of genomic instability in low-complexity-regions, areas that are often neglected during sequencing, during the early stage of the outbreak in Madrid, Spain. We uncovered significant variation in short-tandem repeat areas of the MPXV genome that could be associated with changes in transmissibility. Expression, translation, stability, or function of OPG153 (VACV A26L), OPG204 (VACV B16R) and OPG208 (VACV B19R) could be affected by the changes, in a manner that is consistent with proven “genomic accordion” strategies of OPXV evolution. Intriguingly, while the changes observed in OPG153 stand out as they are located inside a region under high selective pressure for transmission, in a gene that is clearly considered a “core” gene involved in attachment and egress; the changes in OPG208, a serine protease inhibitor-like protein that has been identified as an apoptosis inhibitor, host-range factor and virulence factor; and OPG204, a known inhibitor of the Type I interferon system shown to act as a decoy receptor, could also explain phenotypic changes. Further functional studies to complement this comparative genomic study are urgently needed.
Competing Interest Statement
The work for this study at Instituto de Salud Carlos III was partially funded by Accion Estrategica Impacto clinico y microbiologico del brote por el virus de la viruela del mono en pacientes en Espana (2022): proyecto multicentrico MONKPOX-ESP22 (CIBERINFEC). The work for this study at the GP laboratory was funded by instiutional funds of the Department of Microbiology, Icahn School of Medicine at Mount Sinai in support of Global Health Emerging Pathogen Institute activities. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapuetics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen and Pfizer, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott and Astrazeneca. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work.
Footnotes
Author affiliations updated.
