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].