Macrophages from endotoxin-hyporesponsive (Lpsd) C3H/HeJ mice are permissive for vesicular stomatitis virus because of reduced levels of endogenous interferon: possible mechanism for natural resistance to virus infection.
The C3H/HeJ mouse strain bears an autosomal gene defect, Lpsd, which results in a greatly diminished capacity to respond to endotoxin, the ubiquitous lipopolysaccharide derived from the cell walls of gram-negative bacteria. These mice also exhibit greater susceptibility to a variety of viral and bacterial infections than syngeneic, fully lipopolysaccharide-responsive (Lpsn) mouse strains and possess macrophages with defects in differentiation which are reversed by treatment with exogenous interferon (IFN). To test directly the hypothesis that C3H/HeJ macrophages are deficient in endogenous IFN levels, macrophages from C3H/HeJ (Lpsd) and C3H/OuJ (Lpsn) mice were compared for sensitivity to vesicular stomatitis virus. At a multiplicity of infection of 0.1, C3H/OuJ macrophages were completely refractory to infection, whereas C3H/HeJ macrophages were permissive for replication, and infection resulted in 100% cytopathic effect. These findings were confirmed with a second inbred Lpsn and Lpsd strain pair. Levels of 2',5'-oligoadenylate synthetase were significantly higher in Lpsn cells. C3H/HeJ macrophages, derived from bone marrow precursors under the influence of macrophage colony-stimulating factor, shown previously to induce IFN in macrophages, were as refractory as C3H/OuJ macrophages. Exposure of nonpermissive macrophages to anti-IFN-alpha/beta antibody prior to infection rendered cells permissive. Our findings suggest that endotoxin provides a primary stimulus for the maintenance of normal macrophage differentiation and innate resistance via the induction of endogenous IFN by macrophages.
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000818:Animals; D004731:Endotoxins / Q000494:pharmacology; D007113:Immunity, Innate; D007158:Immunologic Techniques; D007370:Interferon Type I / Q000276:immunology; D007372:Interferons / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H / Q000276:immunology* / Q000382:microbiology; D014721:Vesicular stomatitis Indiana virus / Q000254:growth & development*; D014779:Virus Replication
D004731:Endotoxins; D007370:Interferon Type I; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase