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).