Intradermal immune response after infection with Vaccinia virus

Abstract

Although Vaccinia virus (VACV) was used to eradicate smallpox by dermal vaccination, there is little information available about the immune response induced at the vaccination site. Previously, an intradermal murine model that mimics smallpox vaccination was established. Here, this model was used to investigate which leukocytes are recruited to the infected lesion and what are the kinetics of recruitment. Data presented show that VACV infection induced the infiltration of macrophages, followed by granulocytes and lymphocytes. Up to 4 days post-infection, the major lymphocyte population was TCRcd T cells, but thereafter, there was a large recruitment of CD4 + and CD8 + T cells. Interestingly, the majority of T cells expressed the natural killer-cell marker DX5. This report is the first to characterize the local immune response sequence to VACV infection and represents a benchmark against which the responses induced by genetically modified VACVs may be compared.Vaccinia virus (VACV) is a potent vaccine against smallpox, but its use was discontinued in the 1970s following smallpox eradication. Recently, vaccination of limited numbers of health-care workers was introduced in the USA, the UK and elsewhere in response to a perceived threat of bioterrorism with Variola virus, the aetiological agent of smallpox. Despite worldwide use of VACV as the smallpox vaccine, only recently have studies analysed the systemic immune response induced in animals (Belyakov et al., 2003;Earl et al., 2004;Xu et al., 2004) and humans (Crotty et al., 2003;Frey et al., 2003;Hammarlund et al., 2003;Amara et al., 2004;Belshe et al., 2004; Combadiere et al., 2004;Greenberg et al., 2005; Pütz et al., 2005; Rock et al., 2005) by modern immunological techniques. However, the immune response at the vaccination site remains poorly understood.Previously, an intradermal model in the mouse ear pinnae that mimics dermal vaccination with VACV was developed (Tscharke & Smith, 1999). Following vaccination, no signs of systemic illness were observed and there was little or no virus spread from the ear. Subsequently, this model was used to assess virulence of different strains of VACV, other orthopoxviruses and VACV mutants engineered to lack specific virus genes . Fig. 1(a) shows that this vaccination induced protection against challenge with all doses of VACV strain Western Reserve (WR) tested (up to 10 7 p.f.u.). It was established previously that doses of 10 5 p.f.u. or greater are lethal in this model (Wilcock et al., 1999;Symons et al., 2002;Fogg et al., 2004;Davies et al., 2005). Another report analysed cells that had infiltrated into VACV-infected ears by separation of the ventral and the dorsal dermal sheets and incubation of these on culture medium at 37 uC for 8-10 h (Reading & Smith, 2003). Non-adherent cells that had migrated from the dermal layers were pooled with the loosely adherent cells recovered by a further incubation (20 min) in PBS containing glucose (2 mg ml 21 ), but without calcium and magnesium. With this technique, called the '...

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

“…Although this seems more remote given that VV is not a natural pathogen of mice, VV does encode at least two proteins that have structural similarity to the C-type lectin family that are expressed on the surface of infected cells, namely A33 and A40R (53,54). Additionally, A40R is a virulence factor with effects restricted to the dermal route of inoculation (55), where NK cells are recruited (56).…”

Gamma Interferon-Induced Interferon Regulatory Factor 1-Dependent Antiviral Response Inhibits Vaccinia Virus Replication in Mouse but Not Human Fibroblasts

“…The host range of VACV is much broader than that for ECTV, and although both viruses can be lethal in mice, mice are particularly sensitive to ECTV and less than 1 PFU can be fatal in some strains. Nonetheless, VACV differs from ECTV in that the VACV spread from the primary site of infection is more efficiently restricted in immunocompetent mice (31,76,79). The administration of exogenous IFN-␥ prevents lethal respiratory VACV infection in mice and reduces the virus titer in the lungs about 1,000-fold (41).…”

The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice

“…into the ears of WT or DNGR-1 KO mice, and the size of the lesion was monitored over 22 days. Primary expansion of the virus is controlled by innate immunity, and the virus load peaks at days 4-5, when adaptive immunity begins to take over (36). The adaptive immune response initiates lesion resolution by day 8-10, and healing is complete by 3-4 weeks.…”