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CAST\/EiJ mice have been widely used for studying orthopoxvirus infection. However, the histopathological features of CAST\/EiJ mice with mpox virus (MPXV) and vaccinia virus (VACV) infections have not been fully elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Four group of CAST\/EiJ mice were challenged with low\u2010dose VACV (10\n                      <jats:sup>3<\/jats:sup>\n                      PFU, VACV\u2010L), high\u2010dose VACV (10\n                      <jats:sup>6<\/jats:sup>\n                      PFU, VACV\u2010H), MPXV (10\n                      <jats:sup>6<\/jats:sup>\n                      PFU) or PBS via intraperitoneal route, and the disease signs and body weight were monitored daily. Subsequently, viral loads and titers in the blood and spleen of CAST\/EiJ mice were analyzed via qPCR and TCID\n                      <jats:sub>50<\/jats:sub>\n                      assay. Finally, the spleen samples were analyzed for histopathological, immunohistochemical and RNA\u2010seq.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Herein, we found that VACV\u2010L and MPXV caused splenomegaly via the intraperitoneal route, whereas VACV\u2010H caused rapid lethality with limited splenomegaly. Transcriptome analysis from spleen revealed significant differences in gene expression between VACV\u2010L and VACV\u2010H groups, but the differentially expressed genes induced by splenomegaly between VACV\u2010L and MPXV groups were highly similar. Furthermore, pathway enrichment analysis demonstrated that the VACV\u2010L, VACV\u2010H, and MPXV groups were all associated with the calcium, MAPK, and PI3K\u2010Akt signaling pathway. Compared to the lethal infection observed in VACV\u2010H group, the splenomegaly in the VACV\u2010L and MPXV groups was characterized by extramedullary hematopoiesis and increased macrophages infiltration in the red pulp. Transcriptome analysis of the spleen demonstrated that the Wnt, tumor necrosis factor (TNF), and transforming growth factor \u03b2 (TGF\u2010\u03b2) signaling pathways may promote splenomegaly by modulating granulocyte infiltration and inflammatory responses. Compared to VACV\u2010L group, the limited splenomegaly but lethality in VACV\u2010H\u2010infected mice might be associated with extensive splenic necrosis, diffuse congestion, and hemorrhage in the red pulp, as well as changes in the cGMP\u2010PKG, Ras signaling, and Fc gamma R\u2010mediated phagocytosis pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings systematically compared the pathogenicity of VACV and MPXV in CAST\/EiJ mice, incorporating splenic transcriptome analysis to provide insights into the potential molecular mechanism behind orthopoxvirus\u2010induced splenomegaly in CAST\/EiJ mice.<\/jats:p>\n                  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