Pathogenesis of mpox
The available data describing the pathogenesis of MPXV infection is
limited. Present understanding of MPXV pathogenesis extrapolates from
what is known about smallpox virus infection and animal data (Figure 1).
MPXV enters the body via infection of mucosal epithelial cells or skin
cells. Viral proteins attach to host cells, facilitating membrane fusion
and entry. The human proteins to which poxviruses bind include heparans,
chondroitin, and laminin which are widely expressed among human cell
lines and likely accounts for the virus’ ability to infect a wide range
of cells. The virus replicates in the cytoplasm of host cells at the
site of inoculation and spreads to local lymph nodes.
Immunohistochemical evaluations suggest that fibroblasts and dendritic
cells are the primary targets of MPXV infection within lymphoid tissue.
Infected macrophages then enter the bloodstream producing a
cell-associated viremia. From the bloodstream, MPXV disseminates to the
skin and other organs. Biopsied lesions from human MPXV infections
reveal eosinophilic cytoplasmic inclusions called Guarnieri bodies which
are diagnostic of poxvirus infections. In early-stage lesions,
keratinocytes exhibit balloon-cell degradation with a mixed inflammatory
infiltrate composed of neutrophils and lymphocytes. Advanced lesions
reveal full thickness epidermal necrosis with surrounding inflammatory
infiltrate composed of lymphocytes, neutrophils and eosinophils.
The interplay between MPXV and the immune system, and specifically T
lymphocytes is complex. Early animal data suggest that while MPXV
infects and disseminates in macrophages, it did not appear to infect
lymphocytes. However, levels of circulating CD4+ T cells, CD8+ T cells,
NK cells and B cells all significantly decline in the days following
MPXV infection and do not return to normal levels until 10 days after
infection. Recent human data also suggest an initial decrease in CD4
lymphocytes in early MPXV infection followed by a clonal expansion. MPXV
appears to evade antiviral CD4+ and CD8+T cell responses by directly
suppressing T cell activation. Notably, Vaccinia virus appears to
preferentially bind antigen presenting cells (APCs) and activated T
cells, but not resting T cells. It is unclear if MPXV possesses a
similar tropism.
Importantly, CD4+ T cells appear to play a critical role in protection
against MPXV. Despite vaccination, SIV-infected macaques with CD4+ T
cell counts <300 cells mm-3 were unable to mount an immune
response and died when challenged with MPXV. This vulnerability has
clearly borne out clinically in the recent 2022 outbreak, with PLWH
comprising greater than 80% of the severe cases. Therefore,
reconstitution of the immune system appears critical to recovery and
clearance of the infection (Figure 2).