Viral expression of CCL2 is sufficient to induce demyelination in RAG1-/- mice infected with a neurotropic coronavirus.
Mouse hepatitis virus strain JHM causes a chronic demyelinating disease in susceptible strains of rodents. Demyelination does not develop in infected RAG1-/- (recombination activation gene-deficient) mice but can be induced by several experimental interventions, including adoptive transfer of virus-specific T cells or antibodies. A common feature of demyelination in these models is extensive infiltration of macrophages/microglia into the white matter. The data obtained thus far do not indicate whether macrophage/microglia infiltration, in the absence of T cells or antibody, is sufficient to mediate demyelination. To determine whether the expression of a single macrophage chemoattractant, in the context of virus infection, could initiate the demyelinating process, we engineered a recombinant coronavirus that expressed the chemokine CCL2/monocyte chemoattractant protein-1. CCL2 has been implicated in macrophage infiltration into the central nervous system and is involved in demyelination in many experimental models of demyelination. Extensive macrophage/microglia infiltration and demyelination has developed in RAG1-/- mice infected with this recombinant virus. Thus, these results suggest that the minimal requirement for demyelination is increased expression of a single macrophage-attracting chemokine in the context of an inflammatory milieu, such as that induced by a viral infection.
Kim
Taeg S
TS
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
Perlman
Stanley
S
D000818:Animals; D001483:Base Sequence; D018932:Chemokine CCL2 / Q000235:genetics* / Q000502:physiology*; D018352:Coronavirus Infections / Q000209:etiology*; D004274:DNA, Recombinant / Q000235:genetics; D003711:Demyelinating Diseases / Q000209:etiology*; D015870:Gene Expression; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004274:DNA, Recombinant; D018398:Homeodomain Proteins; D012333:RNA, Messenger; C039919:RNA, recombinant; D011994:Recombinant Proteins; C064658:RAG-1 protein; D012313:RNA