Date Published: December 23, 2015
Publisher: Public Library of Science
Author(s): Isaac G. Sakala, Geeta Chaudhri, Anthony A. Scalzo, Preethi Eldi, Timothy P. Newsome, Robert M. Buller, Gunasegaran Karupiah, David Hugh Evans.
Orthopoxviruses (OPV), including variola, vaccinia, monkeypox, cowpox and ectromelia viruses cause acute infections in their hosts. With the exception of variola virus (VARV), the etiological agent of smallpox, other OPV have been reported to persist in a variety of animal species following natural or experimental infection. Despite the implications and significance for the ecology and epidemiology of diseases these viruses cause, those reports have never been thoroughly investigated. We used the mouse pathogen ectromelia virus (ECTV), the agent of mousepox and a close relative of VARV to investigate virus persistence in inbred mice. We provide evidence that ECTV causes a persistent infection in some susceptible strains of mice in which low levels of virus genomes were detected in various tissues late in infection. The bone marrow (BM) and blood appeared to be key sites of persistence. Contemporaneous with virus persistence, antiviral CD8 T cell responses were demonstrable over the entire 25-week study period, with a change in the immunodominance hierarchy evident during the first 3 weeks. Some virus-encoded host response modifiers were found to modulate virus persistence whereas host genes encoded by the NKC and MHC class I reduced the potential for persistence. When susceptible strains of mice that had apparently recovered from infection were subjected to sustained immunosuppression with cyclophosphamide (CTX), animals succumbed to mousepox with high titers of infectious virus in various organs. CTX treated index mice transmitted virus to, and caused disease in, co-housed naïve mice. The most surprising but significant finding was that immunosuppression of disease-resistant C57BL/6 mice several weeks after recovery from primary infection generated high titers of virus in multiple tissues. Resistant mice showed no evidence of a persistent infection. This is the strongest evidence that ECTV can persist in inbred mice, regardless of their resistance status.
An acute viral infection can result in complete recovery of the host, death or establishment of persistence. The OPV genus is generally believed to cause acute infections. However, some members such as ECTV [1–7], monkeypox virus (MPXV) , cowpox virus (CPXV) [8–10] and vaccinia virus (VACV) [11,12] have been reported to persist for several weeks or months after experimental infection in a variety of animal species that show no clinical signs of disease . Those reports have neither been thoroughly investigated nor their significance understood. If proven correct, they have profound implications for the ecology of OPV and the epidemiology of diseases they cause. One suggestion is that the reports may be a reflection of persistent infection within a population rather than virus persistence in individual animals . VARV causes smallpox in humans but the disease was successfully eradicated through vaccination more than 35 years ago  without any evidence of re-emergence, implying that it does not cause persistent infections.
An acute viral infection can result in complete recovery of the host with or without residual sequelae, death or establishment of virus persistence . Numerous mechanisms can potentially contribute to an acute viral infection becoming persistent but two factors thought to be critical are the effectiveness of host immune response in eliminating virus and subversion of the response by virus-encoded HRM. The OPV generally cause an acute infection in their hosts. However, some OPV, including ECTV, have been reported to persist in various animal species . It has been suggested that this might be a reflection of persistent infection within a population rather than virus persistence in individual animals . Our data indicate that the natural mouse pathogen ECTV can persist in the individual host.