Aurothiolates enhance the replication of Semliki Forest virus in the CNS and the exocrine pancreas

Abstract

The A7(74) strain of Semliki Forest virus (SFV) is avirulent and the L10 strain virulent in adult mice. A7(74) infection of adult mouse brain gives rise to small discrete foci of infection which, in immunocompetent animals, are cleared within 10 days. In contrast L10 infection results in a widespread and fatal central nervous system infection. Aurothiolates are linear, 2-coordinate complexes in which two ligands are covalently bound on either side of a gold nucleus in a +1 oxidation state (gold (I)). Pretreatment of A7(74) infected mice with two distinct aurothiolates (sodium aurothiomalate and aurothioglucose) resulted in signi®cantly increased brain virus titers, and large con¯uent areas of infection in the brain similar to the pattern of infection seen with the L10 strain. The gold (I) moiety of aurothiolates was demonstrated to be the active component, since thiomalic acid when administered alone had no potentiating effect on the infection. Although both aurothiolates allowed productive replication and spread of A7 (74) within the nature mouse brain, enhanced neuronal destruction was not apparent. There were no signi®cant changes in virus distribution in any other tissue except for the exocrine pancreas and the myocardium where widespread infection of the acinar cells and occasional infected myocytes were observed.

The type I interferon system protects mice from Semliki Forest virus by preventing widespread virus dissemination in extraneural tissues, but does not mediate the restricted replication of avirulent virus in central nervous system neurons

“…neurons. We have previously suggested that the restricted replication of A7(74) in the mature neurons of the adult mouse brain is linked to neuronal differentiation and, in particular, to the availability of freshly synthesized intracellular membranes and their constituent lipids (Oliver & Fazakerley, 1998;Oliver et al, 1997;Scallan & Fazakerley, 1999).…”

Pathogenesis of Semliki Forest Virus Encephalitis

“…Of relevance here is the changed course of events following treatment of infected mice with gold compounds. Treatment of adult mice with sodium aurothiomalate and other gold I compounds results in conversion of this normally avirulent infection to a virulent infection (Allner et al, 1974;Bradish et al, 1975;Mehta and Webb, 1982;Gates et al, 1984;Scallan and Fazakerley, 1999). The gold salt is transported to the CNS where it induces smooth membrane production in neurons (Pathak and Webb, 1983a).…”

“…The gold salt is transported to the CNS where it induces smooth membrane production in neurons (Pathak and Webb, 1983a). In mice treated with gold compounds, A7(74) virus replication is no longer restricted in neurons but is productive and spreads rapidly around the brain (Figure 1), resulting in a panencephalitis characteristic of that observed with the virulent L10 virus (Pathak and Webb, 1983a;Scallan and Fazakerley, 1999).…”

“…Prior treatment with GSTM results in rapid spread of A7(74) infection to produce a panencephalitis similar to that seen with the L10 strain of the virus. Modified fromFazakerley et al (1993) andScallan et al (1999), with permission.…”

Amino acid mutations in the replicase protein nsP3 of Semliki Forest virus cumulatively affect neurovirulence

“…Treatment of adult mice with gold sodium thiomalate, which stimulates smooth membrane synthesis in CNS neurons, renders A7(74) infection lethal (Mehta et al, 1990). In the brains of gold sodium thiomalatetreated, A7(74)-infected mice, neuronal processes stained positive for capsid protein, whereas without thiomalate pre-treatment, only cell bodies of A7(74)-infected neurons were positive for capsid protein (Scallan & Fazakerley, 1999). During post-natal axono-and synaptogenesis when endo-and exocytosis are active in the murine olfactory system, A7(74) spreads interneuronally and infection is lethal for young mice, unlike that for adult animals (Oliver & Fazakerley, 1998).…”