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Title: AFRICAN SWINE FEVER VIRUS MULTIGENE FAMILY 360 AND 530 GENES AFFECT HOST INTERFERON RESPONSE

Author
item Afonso, Claudio
item Piccone, Maria
item Zaffuto, Kristin
item Neilan, John
item Kutish, Gerald
item Lu, Zhiqiang
item BALINSKY, COREY - 1940-01-10
item GIBB, TAMMY - USDA-APHIS-PLUM IS.
item Zsak, Laszlo
item Rock, Daniel

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2003
Publication Date: 2/20/2004
Citation: Afonso, C.L., Piccone, M.E., Zaffuto, K., Neilan, J.G., Kutish, G.F., Lu, Z., Balinsky, C.A., Gibb, T.R., Zsak, L., Rock, D.L. 2004. African swine fever virus multigene family 360 and 530 genes affect host interferon response. Journal of Virology. 78(4):1858-1864.

Interpretive Summary: African swine fever (ASF) is a significant disease of domestic swine, characterized by acute hemorrhage and mortality rates approaching 100%. The ability of ASFV to replicate in monocytes and macrophages is a critical factor for viral virulence. ASFV multigene families 360 and 530 genes (MGF360/530) affect viral growth in macrophage cell cultures and virulence in pigs, but the mechanism by which these novel genes affect virus-host interactions is unknown. To investigate MGF360/530 function we have analyzed and compared macrophage transcriptional responses following infection with wild type ASFV (Pr4) and a MGF360/530 deletion mutant Pr4-D35. A swine cDNA microarray containing 7712 macrophage cDNA clones was constructed and used to compare the transcriptional profiles of infected swine macrophages. We identified 38 interferon early response genes that had significantly increased expression levels in Pr4-D35 infected macrophages. Pr4-D35 infected macrophages also produced significantly higher IFN levels than wild type ASFV. These results indicate that MGF360/530 directly or indirectly suppress host IFN responses. The inability to suppress host IFN responses may account for Pr4-D35 growth defect in macrophages and its attenuation in swine. Understanding how these novel MGF360/530 function will lead to improved design of vaccine viruses.

Technical Abstract: African swine fever virus (ASFV) multigene families 360 and 530 genes (MGF360/530) affect viral growth in macrophage cell cultures and virulence in pigs. The mechanism by which these novel genes affect virus-host interactions is unknown. To define MGF360/530 gene function we compared macrophage transcriptional response following infection with parental ASFV (Pr4) and a MGF360/530 deletion mutant (Pr4-D35). A swine cDNA microarray containing 7712 macrophage cDNA clones was constructed and used to compare the transcriptional profiles of swine macrophages infected with Pr4 and Pr4D35 at 3 and 6 hours post-infection (HPI). While at 3 HPI most genes (7564) had similar expression levels in cells infected with either virus, 38 genes had significantly increased (>2.0 fold, p<0.05) mRNA levels in Pr4-D35 infected macrophages. Similar up-regulation of these genes was observed at 6 HPI. Most Pr4-D35 up-regulated genes were part of a type I interferon (IFN) response, or were genes that are normally induced by dsRNA and/or viral infection. Differential expression of IFN early response genes in Pr4-D35 relative to Pr4 was confirmed by northern blot analysis and real time PCR. Analysis of IFN a mRNA and secreted IFN alevels at 3, 8 and 24 HPI revealed undetectable IFN a in mock and Pr4 infected macrophages but significant IFN levels in Pr4-D35. The absence of IFN a in Pr4 infected macrophages suggests that MGF360/530 either directly or indirectly suppresses a type I IFN response. An inability to suppress host type I IFN responses may account for Pr4D35 growth defect in macrophages and its attenuation in swine.