Graduate Student Medical Research Institute, Institute of Integrated Research, Institute of Science Tokyo Bunkyo-Ku, Tokyo, Japan
Abstract: Mpox is an infectious disease caused by the Mpox virus (MPXV). In 2022, a mpox outbreak has occurred, leading the World Health Organization (WHO) to declare a Public Health Emergency of International Concern (PHEIC) in July of that year. The 2022 outbreak-causing MPXV is classified as clade IIb, and is phylogenetically distinct from the endemic MPXV strains, MPXV clade Ia or IIa. MPXV clade IIb is also different from the endemic strains in terms of fatality rate, symptoms, and epidemiological characteristics. However, there has been insufficient molecular biological research on the differences between MPXV clades. In this study, we conducted functional analysis of MPXV genes which are specifically expressed in MPXV-infected cells to elucidate the characteristics of MPXV. Human keratinocytes or human induced pluripotent stem (iPS) cell-derived colon organoids were infected with three MPXV strains, MPXV clade Ia, MPXV clade IIa, and MPXV clade IIb. After infection, RNA was extracted from the cells and RNA-seq analysis was performed. Among the approximately 170 MPXV genes conserved between the three clades, we identified the MPXV gene which is highly expressed in MPXV clade IIb-infected cells, and then performed functional analysis of that gene. We found that the OPG175 gene was highly expressed in MPXV clade IIb-infected keratinocytes and colon organoids. Although the replication efficiency of MPXV clade IIb was lower than that of MPXV clade Ia and IIa, suppression of OPG175 expression significantly upregulated the replication efficiency of MPXV clade IIb. Conversely, we found OPG175 overexpression to enhance the expression of Wnt signaling-related genes and activation of Wnt signaling to decrease the replication efficiency of MPXV. Therefore, high OPG175 expression in MPXV clade IIb-infected cells likely inhibits MPXV replication via activation of Wnt signaling.
Funding Source: This research was supported by the iPS Cell Research Fund, JSPS Core-to-Core Program (A. Advanced Research Networks), and the Japan Agency for Medical Research and Development (AMED) (JP21gm1610005, JP23fk0108583, JP23jf0126002).
