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. 2012;158(2):196-205.
doi: 10.1159/000330647. Epub 2012 Jan 26.

Susceptibility to vaccinia virus infection and spread in mice is determined by age at infection, allergen sensitization and mast cell status

Joanne Domenico  1 , Joseph J Lucas, Mayumi Fujita, Erwin W Gelfand
Affiliations

Susceptibility to vaccinia virus infection and spread in mice is determined by age at infection, allergen sensitization and mast cell status

Joanne Domenico et al. Int Arch Allergy Immunol. 2012.

Abstract

Background: Patients, especially young children, with atopic dermatitis are at an increased risk of developing eczema vaccinatum, a severe reaction to the smallpox vaccine, either through direct vaccination or indirect contact with a person recently vaccinated.

Methods: Using a mouse model of infection, the severity of vaccinia-induced lesions was assessed from their appearance and viral DNA content. The response to vaccinia inoculation was assessed in young and adult mice, allergen-sensitized mice, and in mast cell-deficient mice.

Results: Young age, sensitization to an allergen prior to infection, and a mast cell deficit, accomplished by using mast cell-deficient mice, resulted in more severe viral lesions at the site of inoculation, according to lesion appearance and viral DNA content. All three factors combined demonstrated maximal susceptibility, characterized by the severity of primary lesions and the development of secondary (satellite) lesions, as occurs in eczema vaccinatum in humans. Resistance to the appearance of satellite lesions could be restored by adoptive transfer of bone marrow-derived mast cells from either wild-type or cathelicidin-related antimicrobial peptide-deficient mice. Primary lesions were more severe following the latter transfer, indicating that cathelicidin-related antimicrobial peptide does contribute to the protective activity of mast cells against infection.

Conclusions: The combination of young age, allergen sensitization and a mast cell deficit resulted in the most severe lesions, including satellite lesions. Understanding the factors determining the relative resistance/sensitivity to vaccinia virus will aid in the development of strategies for preventing and treating adverse reactions which can occur after smallpox vaccination.

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Figures

Fig. 1
Fig. 1
Young age increases susceptibility to VV in Balb/c mice. Severity of primary lesion appearance in 10-week-old mice (a, b) was compared to that of 4-week-old mice (c, d) at 5 days after inoculation with VV. The 4-week-old mice had lesions that had healed less and showed greater exudates than the lesions of the 10-week-old mice. e When assayed at 7 days after infection, the primary lesions of 4-week-old Balb/c mice contained more VV DNA than their 10-week-old counterparts (n = 6 for each group). * p = 0.02.
Fig. 2
Fig. 2
Young age increases susceptibility to VV in C57BL/6 mice. Severity of primary lesion appearance in 10-week-old mice (a, b) was compared to that of 4-week-old mice (c, d) at 5 days after inoculation with VV. The 4-week-old mice had lesions that had healed less and showed greater exudates than the lesions of the 10-week-old mice. e When assayed at 7 days after infection, the primary lesions of 4-week-old C57BL/6 mice contained more VV DNA than their 10-week-old counterparts (n = 7 for each group). * p = 0.04.
Fig. 3
Fig. 3
Lack of mast cells increases susceptibility to VV, shown by comparison of viral DNA content in primary lesions of young KitW-sh/W-shmast cell-deficient and young C57BL/6 WT mice. Visual inspection showed no dramatic differences between the primary lesions of the WT, 4-week-old C57BL/6 mice (a, b) and the 4-week-old, mast cell-deficient, KitW-sh/W-sh mice (c, d) at 5 days after inoculation with VV. e However, at 7 days after infection, the primary lesions of the 4-week-old KitW-sh/W-sh mice (n = 9) contained more VV DNA than the primary lesions of the 4-week-old C57BL/6 mice (n = 10). * p = 0.01.
Fig. 4
Fig. 4
Combination of young age, sensitization and mast cell deficit increases susceptibility to VV infection, indicated by severity of primary lesions, satellite lesions and viral DNA content. Five days after infection, primary lesions of the adult (10-week-old), sensitized KitW-sh/W-sh mice were limited to the site of inoculation (a, b) while primary lesions of the young (4-week-old) mice appeared more severe, with spreading outside of the inoculation site (c, d). Satellite lesions (arrows) were seen in all young mice compared to no satellite lesions in the adult mice. e Seven days after infection, the primary lesions of the young, sensitized KitW-sh/W-sh mice (n = 13) contained more VV DNA than was found in lesions from the adult, sensitized KitW-sh/W-sh group (n = 7). * p = 0.04.
Fig. 5
Fig. 5
Reconstitution of resistance to VV infection following adoptive transfer of BMMCs into mast cell-deficient mice. Mast cells from either C57BL/6 (d, e) or CRAMP-deficient (Cnlp−/−) mice (g, h) were adoptively transferred to young, sensitized KitW-sh/W-shmice. Lesions appeared worse in the KitW-sh/W-shmice that did not receive mast cells (a, b) with infection forming satellite lesions. Lesions from mice that received BMMCs from Cnlp−/− mice (g, h) appeared worse than those that received BMMCs from C57BL/6 WT mice (d, e). Successful mast cell transfer was confirmed by Astra Blue staining of skin biopsies (f, i). No mast cells were detected in KitW-sh/W-sh mice that did not receive mast cells (c). The mice and tissue shown are representative of experiments with KitW-sh/W-shmice that did not receive mast cells (n = 16), KitW-sh/W-shmice which received WT mast cells (n = 19) and KitW-sh/W-shmice which received Cnlp−/− mast cells (n = 14). c, f, i ×200.
Fig. 6
Fig. 6
Histopathology of skin adjacent to primary VV-induced lesions. a The appearance of the skin in uninfected KitW-sh/W-sh mice. Dense cellular infiltrates were seen in young sensitized mast cell-deficient infected KitW-sh/W-shanimals (b), which were greatly reduced following adoptive transfer of BMMCs from WT C57BL/6 animals (c), and much less so following the transfer of BMMCs from CRAMP−/− animals (d). b–d insets Cellular composition of the infiltrates. The sections are stained with H&E stain. The tissue sections are representative of experiments with KitW-sh/W-shmice that did not receive mast cells (n = 16), KitW-sh/W-shmice which received WT mast cells (n = 19) and KitW-sh/W-shmice which received Cnlp−/− CRAMP−/− mast cells (n = 14). a–d ×100. Insets ×1,000.
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