Abstract
Adverse events upon smallpox vaccination with fully-replicative strains of Vaccinia virus (VACV) comprise an array of clinical manifestations that occur primarily in immunocompromised patients leading to significant host morbidity/mortality. The expansion of immune-suppressed populations and the possible release of Variola virus as a bioterrorist act have given rise to concerns over vaccination complications should more widespread vaccination be reinitiated. Our goal was to evaluate the components of the host immune system that are sufficient to prevent morbidity/mortality in a murine model of tail scarification, which mimics immunological and clinical features of smallpox vaccination in humans. Infection of C57BL/6 wild-type mice led to a strictly localized infection, with complete viral clearance by day 28 p.i. On the other hand, infection of T and B-cell deficient mice (Rag1 −/−) produced a severe disease, with uncontrolled viral replication at the inoculation site and dissemination to internal organs. Infection of B-cell deficient animals (µMT) produced no mortality. However, viral clearance in µMT animals was delayed compared to WT animals, with detectable viral titers in tail and internal organs late in infection. Treatment of Rag1 −/− with rabbit hyperimmune anti-vaccinia serum had a subtle effect on the morbidity/mortality of this strain, but it was effective in reduce viral titers in ovaries. Finally, NUDE athymic mice showed a similar outcome of infection as Rag1 −/−, and passive transfer of WT T cells to Rag1 −/− animals proved fully effective in preventing morbidity/mortality. These results strongly suggest that both T and B cells are important in the immune response to primary VACV infection in mice, and that T-cells are required to control the infection at the inoculation site and providing help for B-cells to produce antibodies, which help to prevent viral dissemination. These insights might prove helpful to better identify individuals with higher risk of complications after infection with poxvirus.
Highlights
The Vaccinia virus (VACV) is a member of Poxviridae family and the Orthopoxvirus genus, which includes several human pathogens such as Variola virus (VARV), Cowpox virus (CPXV), Monkeypox virus (MPXV), and the mouse-specific pathogen Ectromelia virus (ECTV)[1]
It is difficult to extrapolate this information from current animal model studies, as most studies try to model systemic orthopoxvirus disease in humans and have used routes of administration that produce a systemic infection in immunocompetent mice, such as intranasal and intraperitoneal routes with high virus inoculation [6,8]
To test the role of inflammatory cytokines in this model, animals deficient in IL-12/23 or TNF were infected with VACV-WR by tail scarification
Summary
The Vaccinia virus (VACV) is a member of Poxviridae family and the Orthopoxvirus genus, which includes several human pathogens such as Variola virus (VARV), Cowpox virus (CPXV), Monkeypox virus (MPXV), and the mouse-specific pathogen Ectromelia virus (ECTV)[1]. The use of live, replicative VACV was effective in providing protection against smallpox through the elicitation of strong acute immune responses, followed by viral replication control and induction of immune memory [2]. Vaccination in humans is performed by inoculating the virus via multiple skin punctures that produce a localized infection, without systemic involvement in immunocompetent patients ( traces of blood borne viral DNA have been seen in a minority of patients in a few studies), but can cause a wide range of complications in immunocompromised individuals [9]. Tail scarification (ts) infection in mice provides a useful model to study the complications derived from VACV inoculation, since it resembles the immunological and virological parameters of human smallpox vaccination [10]
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