Currently, there is a paucity of information regarding the molecular pathogenesis for many high-consequence pathogens (HCPs) that pose direct threats to public health and security both nationally and internationally. For example, variola virus (VARV), the etiologic agent of smallpox, was responsible for ~500 million human fatalities in the 20(th) century prior to its successful eradication in May 1980 [1]. Following the cessation of routine vaccinia virus (VACV) vaccination, a significant portion of the global population has been left vulnerable to VARV. This has resulted in significant concerns regarding the potential release of VARV, or another closely related orthopoxvirus, such as monkeypox virus (MPXV), to an increasingly vulnerable population. This article is protected by copyright. All rights reserved.