The role of the Type I interferon response in the resistance of mice to filovirus infection

Adult immunocompetent mice inoculated with Ebola (EBO) or Marburg (MBG) vir us do not become ill. A suckling-mouse-passaged variant of EBO Zaire '76 (' mouse-adapted EBO-Z') causes rapidly lethal infection in adult mice after intraperitoneal (i.p.) inoculation, but does not cause apparent disease whe n inoculated subcutaneously (s.c.). A series of experiments showed that bot h forms of resistance to infection are mediated by the Type I interferon re sponse. Mice lacking the cell-surface IFN-alpha/beta receptor died within a week after inoculation of EBO-Z '76, EBO Sudan, MBG Musoke or MBG Ravn, or after s.c. challenge with mouse-adapted EBO-Z. EBO Reston and EBO Ivory Co ast did not cause illness, but immunized the mice against subsequent challe nge with mouse-adapted EBO-Z. Normal adult mice treated with antibodies aga inst murine IFN-alpha/beta could also be lethally infected with i.p.-inocul ated EBO-Z '76 or EBO Sudan and with s.c.-inoculated mouse-adapted EBO-Z. S evere combined immunodeficient (SCID) mice became ill 3-4 weeks after inocu lation with EBO-Z '76, EBO Sudan or MBG Ravn, but not the other viruses. Tr eatment with anti-IFN-alpha/beta antibodies markedly accelerated the course of EBO-Z '76 infection. Antibody treatment blocked the effect of a potent antiviral drug, 3-deazaneplanocin A, indicating that successful filovirus t herapy may require the active participation of the Type I IFN response. Mic e lacking an IFN-alpha/beta response resemble primates in their susceptibil ity to rapidly progressive, overwhelming filovirus infection. The outcome o f filovirus transfer between animal species appears to be determined by int eractions between the virus and the innate immune response.