Human MxA Protein Protects Mice Lacking a Functional Alpha/Beta Interferon System against La Crosse Virus and Other Lethal Viral Infections

Abstract

The human MxA protein is part of the antiviral state induced by alpha/beta interferon (IFN-α/β). MxA inhibits the multiplication of several RNA viruses in cell culture. However, its antiviral potential in vivo has not yet been fully explored. We have generated MxA-transgenic mice that lack a functional IFN system by crossing MxA-transgenic mice constitutively expressing MxA with genetically targeted (knockout) mice lacking the β subunit of the IFN-α/β receptor (IFNAR-1−/− mice). These mice are an ideal animal model to investigate the unique antiviral activity of human MxA in vivo, because they are unable to express other IFN-induced proteins. Here, we show that MxA confers resistance to Thogoto virus, La Crosse virus, and Semliki Forest virus. No Thogoto virus progeny was detectable in MxA-transgenic mice, indicating an efficient block of virus replication at the primary site of infection. In the case of La Crosse virus, MxA restricted invasion of the central nervous system. In contrast, Semliki Forest virus multiplication in the brain was detectable in both MxA-expressing and nonexpressing IFNAR-1−/− mice. However, viral titers were clearly reduced in MxA-transgenic mice. Our results demonstrate that MxA does not need the help of other IFN-induced proteins for activity but is a powerful antiviral agent on its own. Moreover, the results suggest that MxA may protect humans from potential fatal infections by La Crosse virus and other viral pathogens.

The role of IL-12, IL-23 and IFN-γ in immunity to viruses

“…IFN-␣/␤ is considered to play a major role in antiviral defense [152]. For experimental infections, anti-IFN␣/␤ antibody-treated mice [152] and IFN␣/␤ receptor KO mice [104,112,[153][154][155][156][157], as well as mice deficient in both IFN␣/␤ and IFN-␥ receptors [5,55], STAT1 [158,159] and STAT2 [160] showed marked sensitivity to a broad range of DNA and RNA viruses. However, the IL-12/IL-23 and IFN-␥ axis is interconnected with IFN␣/␤ in the antiviral defense.…”

The interferon response circuit: Induction and suppression by pathogenic viruses

“…Transgenic introduction of mouse or human Mx is sufficient to turn susceptible mice into resistant animals (Arnheiter et al, 1990;Pavlovic et al, 1995). More importantly, constitutive expression of human MxA in an otherwise IFN-non-responsive animal confers full protection, demonstrating the exquisite power of a single effector molecule of the human IFN system in an otherwise susceptible host (Hefti et al, 1999). A single autosomal dominant gene locus, designated Flv/Wnv, is responsible for natural resistance of mice against infection with West Nile virus (WNV) and other flaviviruses (Brinton and Perelygin, 2003).…”

“…Mx proteins belong to the superfamily of dynamin-like large GTPases and have been discovered as mediators of genetic resistance against orthomyxoviruses in mice. Their importance for host survival following infection with certain RNA viruses has been amply demonstrated (Arnheiter et al, 1996;Hefti et al, 1999;Pavlovic et al, 1995) but their exact mode of action is still unknown. The relevance of the OAS/RNaseL and PKR Fig.…”

Interferon, Mx, and viral countermeasures

“…The protective power of the human MxA GTPase is best demonstrated in MxA-transgenic mice. Human MxA was sufficient to turn susceptible Mx1-negative mice into resistant animals [59]. Moreover, even the constitutive expression of MxA in otherwise IFN-nonresponsive IFNAR 0/0 animals conferred full resistance against disease, thus highlighting the importance of the human Mx system for antiviral defense [59].…”