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Mx1 but not MxA confers resistance against tick-borne Dhori virus in mice
1Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Germany.
Abstract:
The interferon-induced nuclear Mx1 protein is responsible for innate resistance of mice to influenza virus. It has been unclear why mice are equipped with a powerful and specific defense mechanism against influenza viruses for which they are not natural hosts. Here, we show that Dhori virus, an influenza-like virus transmitted by ticks and known to infect small mammals, is sensitive to the Mx1 resistance mechanism. Influenza virus-susceptible BALB/c and C57BL/6 mice (lacking a functional Mx1 gene) developed severe disease symptoms and died within a few days after intraperitoneal infection with a lethal dose of Dhori virus. In contrast, Mx1(+)-congenic, influenza virus-resistant BALB.A2G-Mx1 and B6.A2G-Mx1 mice remained healthy and survived. The Mx1 resistance phenotype was expressed in cultured peritoneal macrophages and interferon-treated embryonic cells obtained from these mice. Moreover, stable lines of transfected mouse 3T3 cells constitutively expressing Mx1 protein were protected from Dhori virus infection. The MxA protein of human cells shows a high degree of sequence similarity to Mx1 but, unlike Mx1, inhibits a broad range of RNA viruses. Transgenic mice that permanently express the human MxA protein in various organs became resistant to infection with Thogoto virus but remained fully susceptible to Dhori virus. These in vivo results show that DHO virus is unique in being resistant to human MxA but susceptible to mouse Mx1 protein. They further indicate that the Mx1 system functions as a potent defense mechanism against tick-borne influenza-like viruses in mice.
Insights
Mice possess a specific defense against influenza-like viruses, mediated by the Mx1 protein. This study reveals Mx1 protein protects mice from Dhori virus, a tick-borne pathogen, highlighting its role in innate immunity against such threats.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- The Mx1 protein in mice confers innate resistance to influenza viruses.
- The evolutionary advantage of this specific defense against non-natural hosts remained unclear.
Purpose of the Study:
- To investigate the role of the mouse Mx1 protein in resistance to Dhori virus, an influenza-like virus.
- To compare the efficacy of mouse Mx1 and human MxA proteins against Dhori virus.
Main Methods:
- Infection of influenza virus-susceptible and Mx1-resistant mouse strains with Dhori virus.
- Testing Mx1 resistance in cultured mouse cells (macrophages, embryonic cells, 3T3 cell lines).
- Assessing Dhori virus susceptibility in transgenic mice expressing human MxA protein.
Main Results:
- Mice lacking functional Mx1 protein (BALB/c, C57BL/6) succumbed to Dhori virus infection, while Mx1-expressing mice (BALB.A2G-Mx1, B6.A2G-Mx1) survived.
- Mx1-mediated resistance was observed in various mouse cell types.
- Human MxA protein did not confer resistance to Dhori virus in transgenic mice, unlike its resistance to Thogoto virus.
Conclusions:
- The mouse Mx1 protein is a key defense mechanism against Dhori virus, a tick-borne influenza-like virus.
- Dhori virus exhibits unique resistance to human MxA but susceptibility to mouse Mx1, differentiating it from other viruses.
- The Mx1 system provides potent innate immunity against specific tick-borne viral threats in mice.