Pathogenesis of MPXV
MPXV may enter the host via the oropharynx, nasopharynx, or intradermal pathways. In the respiratory tract, the MPXV can infect airway epithelial cells, while in the skin, the virus infects keratinocytes, fibroblasts, and endothelial cells, establishing productive and cytopathic infections. In addition, antigen-presenting cells such as dendritic cells, Langerhans cells, and macrophages in the skin are infected by abortion, allowing them to survive long enough to carry the antigen to draining lymph nodes [24]. After a period of initial viremia, the virus spreads to other body organs. MPXV is a DNA virus, but its life cycle occurs in the cytoplasm and involves six stages, namely virus entry, uncoating, DNA replication, assembly, morphogenesis, and release (Fig. 4). There are two different infectious virus particles in MPXV: intracellular mature virus (IMV) and extracellular enveloped virus (EEV) [25]. IMVs with an outer lipoprotein envelope are responsible for transmission between hosts, and they enter the host cell by microcellular action or fusion and are released only during host cell lysis. In contrast, EEVs with an antigenically distinct outer triple envelope are responsible for transmission within the host, and they enter the host by fusion and are released by exocytosis [26]. MPXV replication is initiated by multi-subunit DNA-dependent RNA polymerases encoded by MPXV, which then translates early, intermediate, and late proteins on the host ribosome [27]. Late proteins are assembled to form the infectious virus IMVs, which are then encapsulated by a double membrane from the Golgi apparatus to form the intracellular enveloped virus (IEVs). IEVs lose their outer membrane wrapping by triggering actin polymerization and subsequently fuse with the cell membrane to form cell-associated enveloped viruses and eventually release to form EEVs [28]. Notably, cellular proteins such as COG4, COG7, vesicle protein sorting proteins VPS52 and VPS54 and some toxicity-related genomic regions such as ORF17-31, 181-192 are essential for MPXV infection, but how these proteins or genes collaborate to regulate MPXV-induced host pathogenesis is still unclear [29–31].