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Title:African swine fever virus CD2v protein induces β-interferon expression and apoptosis in swine peripheral blood mononuclear cells
Author(s):Chaulagain, Sabal
Director of Research:Rock, Daniel L
Doctoral Committee Chair(s):Rock, Daniel L
Doctoral Committee Member(s):Delhon, Gustavo A; Zuckermann, Federico A; Jarosinski, Keith W
Department / Program:Pathobiology
Discipline:VMS - Pathobiology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):African swine fever virus
CD2v
Interferon-β
NF-κB
CD58
Lymphocyte
Macrophage
Apoptosis
Pathogenesis
Abstract:African swine fever (ASF) is an acute viral hemorrhagic disease of domestic swine with mortality rates approaching 100%. Devastating ASF outbreaks and continuing epidemics starting in the Caucasus region, and now in the Russia Federation, Europe, China and other parts of Southeast Asia (2007 to date) highlight its significance. ASFV, the sole member of the Asfarviridae (Asfar, African swine fever, and related viruses), is a large, enveloped and genetically complex virus containing a double-stranded DNA genome of approximately 190 kilobase pairs, which encodes for over 170 proteins. Aspects of genome structure and replication strategy are shared between ASFV and other large dsDNA viruses, most notably poxviruses (Tulman, Delhon & Rock, 2009). ASF in domestic pigs occurs in several forms, ranging from highly lethal (100% mortality) to subclinical. Hemostatic and hemodynamic changes (hemorrhage, edema, ascites, and shock) resulting from intravascular activation of coagulation are observed in pigs infected with highly virulent ASFV strains (Montgomery, 1921; Detray, 1957; Oura et al., 1998a). ASFV infects cells of the mononuclear-phagocytic system, including highly differentiated fixed-tissue macrophages and specific lineages of reticular cells, and highly virulent strains induce extensive damage in affected tissues (Moulton et al., 1968; Gomez-Villamandos et al., 2013). The ability of ASFV to replicate and induce marked cytopathology in these cell types in vivo appears to be a critical factor in ASFV virulence. A characteristic of acute ASF is the severe lymphoid tissue destruction and massive lymphocyte depletion observed in infected pigs. As lymphocytes do not support ASFV replication, factors released or secreted by infected macrophages have been implicated in triggering lymphocyte apoptosis (Gomez-Villamandos et al., 1995; Carrasco et al., 1996a; Gomez del Moral et al., 1999; Slaguero et al., 2002; Salguero et al., 2005). However, viral and host factors responsible are poorly understood. Here, we found that CD2v expression in swine PK15 cells induces NF-κB-dependent IFN-β and ISGs transcription, and an antiviral state. Similar results were observed in purified CD2v protein treated swine PBMCs and macrophages, the major ASFV target cell. Notably, treatment of swine PBMCs and macrophages with CD2v protein induced apoptosis. Immunoprecipitation and co-localization studies revealed that CD2v interacts with CD58, the natural host CD2 ligand. And, CD58 knockdown in cells or treatment of cells with an NF-κB inhibitor significantly reduced CD2v-mediated NF-κB activation and IFN-β induction. Further, antibodies directed against CD2v inhibited CD2v-induced NF-κB activation and IFN-β transcription in cells. Overall, results indicate that ASFV CD2v activates NF-κB which induces IFN signaling and apoptosis in swine lymphocytes /macrophages. In conclusion, data indicate a previously undescribed function for CD2v and suggest the protein is a contributing factor to the lymphoid tissue damage and lymphocyte depletion observed during acute ASFV infection.
Issue Date:2021-07-13
Type:Thesis
URI:http://hdl.handle.net/2142/113301
Rights Information:Copyright 2021 Sabal Chaulagain
Date Available in IDEALS:2022-01-12
Date Deposited:2021-08


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