Variola virus and clade I monkeypox virus differentially modulate cellular responses longitudinally in monocytes during infection.

Variola virus (VARV), the etiological agent of smallpox, had enormous impacts on global health prior to its eradication. In the absence of global vaccination programs, monkeypox virus (MPXV) has become a growing public health threat that includes endemic regions of Sub-Saharan Africa and, more recently, non-endemic regions following the identification of clade IIb MPXV in many global regions. While human mpox resembles smallpox in clinical presentation, there are considerable knowledge gaps regarding conservation of molecular mechanisms of pathogenesis between these two human orthopoxviruses. Given this paucity of knowledge, we sought to compare MPXV and VARV infections in human monocytes through kinome analysis. We performed a longitudinal analysis of host cellular responses to VARV infection in human monocytes as well as a comparative analysis to clade I MPXV-mediated responses. While infection with either virus resulted in greater activation of cellular responses early in the course of infection as compared to later time points, several key differences in specific cell signaling events were identified and validated through the analysis of inhibition of kinases and cell signaling pathways on viral infection. These observations will help in the design and development of pan-orthopoxvirus therapeutics. To our knowledge, this is the first assessment of host cell signaling responses during VARV infection and comparison of host cell signaling response modulation by VARV and clade I MPXV.