title: Mousepox in the C57BL/6 strain provides an improved model for evaluating anti-poxvirus therapies.
abstract: The intranasal lethal mousepox model employing the A/Ncr mouse strain is used to evaluate anti-orthopoxvirus therapies. These infections mimic large droplet transmission and result in 100% mortality within 7-10 days with as little as 1 PFU of ectromelia virus. Unlike the A/Ncr model, humans are less susceptible to lethal respiratory infections with variola virus and monkeypox virus as demonstrated by their lower mortality rates. In this study we show that a low dose intranasal infection of C57BL/6 mice results in 60-80% mortality and better models smallpox. Comparing CMX001 (HDP-cidofovir) efficacy in the A/Ncr strain and the C57BL/6 strain revealed that delayed treatment with CMX001 is more efficacious at preventing severe disease in the C57BL/6 strain. The increased efficacy of CMX001 in C57BL/6 over A/Ncr following an intranasal infection with ectromelia appears to be mediated by a stronger Th1 cell mediated response. Following footpad infection we show that the C57BL/6 strain has earlier and more robust transcriptional activity, Th1 cytokine secretions, antigen presenting activity and IFNgamma splenic CD8+ T cell responses as compared to the A/Ncr strain. As a result of the enhanced immune response in the C57BL/6 strain, non-lethal intradermal ectromelia infections can therapeutically protect up to 3 days following a homologous, lethal intranasal infection - much like how smallpox vaccination can protect humans for up to 4 days following intranasal variola infection.
authors.affiliation: Saint Louis University Medical School, MO 63104, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Parker
authors.forename: Akbar M
authors.initials: AM
authors.lastname: Siddiqui
authors.forename: Christina
authors.initials: C
authors.lastname: Oberle
authors.forename: Ed
authors.initials: E
authors.lastname: Hembrador
authors.forename: Randall
authors.initials: R
authors.lastname: Lanier
authors.forename: George
authors.initials: G
authors.lastname: Painter
authors.forename: Alice
authors.initials: A
authors.lastname: Robertson
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000276:immunology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004481:Ectromelia virus / Q000502:physiology*; D004482:Ectromelia, Infectious / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine