The type I interferon system protects mice from Semliki Forest virus by preventing widespread virus dissemination in extraneural tissues, but does not mediate the restricted replication of avirulent virus in central nervous system neurons

Abstract

Semliki Forest virus (SFV) infection of the mouse provides a powerful model to study the pathogenesis of virus encephalitis. SFV and other alphavirus-based vector systems are increasingly used in biotechnology and medicine. This study analysed the strong susceptibility of this virus to type I interferon (IFN) responses. Following intraperitoneal infection of adult mice, SFV strain A7(74) was efficiently (100 %) neuroinvasive. In contrast, SFV4 was poorly (21 %) neuroinvasive. Upon entry into the brain, both viruses activated type I IFN responses. As determined by quantitative RT-PCR, activation of the IFN-a gene was proportional to virus RNA load. An intact type I IFN system was required for protection against both strains of SFV. IFN strongly curtailed virus spread in many cell types and in many tissues. In mice with an intact type I IFN system, infected cells were rarely observed and tissue tropism was difficult to determine. In the absence of a functional type I IFN system, the tropism and the potential for rapid and widespread infection of this virus was revealed. Virus infection was readily observed in the myocardium, endocardium, exocrine pancreas, adipose tissue, smooth muscle cells and in the brain in meningeal cells, ependymal cells and oligodendrocytes. In the brains of mice with and without type I IFN responses, virus infection of neurons remained rare and focal, indicating that the previously described restricted replication of SFV A7(74) in neurons is not mediated by type I IFN responses. INTRODUCTIONSemliki Forest virus (SFV) is a mosquito-borne virus that naturally circulates in sub-Saharan Africa. The virus is an alphavirus of the family Togaviridae. Natural human and equine infections have been described (Mathiot et al., 1990). The virus is closely related to Chikungunya virus, responsible recently for an outbreak of severe arthralgia in the islands of the Indian Ocean (Schuffenecker et al., 2006). Other alphaviruses include Sindbis virus in North Africa and Europe; Eastern, Western and Venezuelan equine encephalitis viruses in the Americas and Ross River virus in Australia. SFV infection of laboratory mice provides a tractable model system for the study of virus pathogenesis and in particular virus encephalitis (Fazakerley, 2004). Virulence in mice has been characterized for several natural isolates and their laboratory-passaged strains (Bradish et al., 1971). The most commonly studied strains include A7 and A7(74), which are avirulent in adult mice, and L10 and the prototype, which are virulent in adult mice. All strains of SFV are virulent in neonatal or young suckling mice (Bradish et al., 1971;Pusztai et al., 1971;Seamer et al., 1967).The most characterized avirulent strain of SFV, A7(74), is virulent in mice infected at the age of 11 days or less, but is avirulent in older mice; virus dissemination in the central nervous system (CNS) is increasingly restricted with age (Oliver et al., 1997). In 4-5-week-old mice, intraperitoneal inoculation of SFV A7(74) results in a high-titre plasma vira...

Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

“…SFV4 did not infect astrocytes (Fig. 3J-L), which is in accordance with previous reports (37). In immune competent mice SFV4 is also known not to infect any other organ except CNS (37), therefore we believe that SFV4miRT has an improved safety profile.…”

MicroRNA-Attenuated Clone of Virulent Semliki Forest Virus Overcomes Antiviral Type I Interferon in Resistant Mouse CT-2A Glioma

“…3) despite being highly neurovirulent for adult mice (22). Thus, the nsp3-dependent neurovirulence factors are not (11,29). Moreover, we found no difference in STAT1 inhibition between L10 and SFV4 that would explain the increased neurovirulence of L10 ( Fig.…”

A Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors

“…Alphaviruses are very sensitive to the action of type I IFNs, and it would be reasonable to think that expression of these cytokines from such a recombinant vector could hinder its production and activity. 31,32 On the other hand, alphaviruses induce the release of type I IFNs in infected cells and expression of more IFNa from the vector may be redundant for therapeutic purposes. 31,32,36 In spite of these potential drawbacks, we have shown that it is possible to produce high titers of recombinant SFV vectors expressing IFNa in BHK cells.…”

“…31,32 On the other hand, alphaviruses induce the release of type I IFNs in infected cells and expression of more IFNa from the vector may be redundant for therapeutic purposes. 31,32,36 In spite of these potential drawbacks, we have shown that it is possible to produce high titers of recombinant SFV vectors expressing IFNa in BHK cells. The most likely explanation for achieving this high SFV-IFN production is the fact that BHK cells have been shown to be defective in type I IFN responses.…”

“…In this study, we developed a SFV vector expressing murine IFNa1 (SFV-IFN) and evaluated its antitumor effects in the TC-1 tumor model. As alphaviruses are strongly inhibited by type I IFN responses, 31,32 the in vitro production and the in vivo efficacy of a recombinant alphavirus vector expressing IFNa represented a technical challenge. In spite of this, we show that SFVIFNa can be produced to normal titers, and can infect the TC-1 cell line and produce IFNa.…”