Cytokine patterns in a comparative model of arenavirus infection: Implications for virulence and control of viral replication

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Title: Cytokine patterns in a comparative model of arenavirus infection: Implications for virulence and control of viral replication
Author: Erin P. Scott
Abstract: Guinea pig infection with the arenavirus Pichinde provides an animal model for human Lassa fever , a disease that affects 300 ,000 to 500 ,000 people a year in western Africa . Low passage Pichinde virus (P2 ) induces a mild disease with low viremia , while high passage Pichinde (P18 ) induces a severe disease with high viremia , ending in terminal shock . We hypothesized that severe disease would be associated with a suppression of potentially antiviral cytokines early in infection , and high levels of potentially pathogenic pro -inflammatory cytokines late in infection . Cytokine responses to P2 and P18 infection were measured from primary guinea pig peritoneal macrophages (PM ) in vitro when measured by real time RT -PCR . In general , neither P2 nor P18 infection altered cytokine production from unstimulated PM . P18 infected PM did have lower mRNA levels of IL -1beta , IL -12p40 , and MCP -1 after LPS addition when compared to P2 infected PM . During experimental guinea pig infection , P18 infection was associated with markedly increased IFN -gamma and MCP -1 mRNA levels from the initial peritoneal target cells relative to P2 . P18 infected peritoneal cells had slightly decreased TNF -alpha , IL -8 , and IL -12p40 transcripts relative to mock infected peritoneal cells . Late in infection , P18 infected spleens and livers had similar cytokine patterns relative to P2 , but P18 infected PBL had decreased TNF -alpha , IFN -gamma , and RANTES transcripts . We also examined the ability of a decoy AP -1 thioaptamer , XBY -S2 , to alter morbidity , mortality , and cytokine expression during P18 infection of guinea pigs . After two doses of XBY -S2 , 50 % (p= .024 ) of treated guinea pigs survived infection and had undetectable viremia . XBY -S2 -treated P18 infected guinea pigs over time had overall increased cytokine mRNA expression of TNF -alpha , IL -8 , IL -1beta , and IL -10 compared to PBS -treated P18 infected guinea pigs . A suppression of PBL IL -1beta and RANTES mRNA at day 12 of P18 infection was repeatedly observed . Conclusions from these experiments are 1 ) macrophage -derived cytokines do not explain the differential replication of P2 and P18 viruses , 2 ) high levels of IFN -gamma and MCP -1 may contribute to virulence of P18 virus , 3 ) over -expression of pro -inflammatory cytokines in PBL , liver , or spleen is not associated with terminal shock , 4 ) boosting of pro -inflammatory cytokines by an AP -1 aptamer correlates with reduced viremia and survival of P18 infection .
URI: http : / /hdl .handle .net /2152 .3 /163
Date: 2005-07-12

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Cytokine patterns in a comparative model of arenavirus infection: Implications for virulence and control of viral replication. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /163 .

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