IKKα-Mediated Noncanonical NF-κB Signaling Is Required To Support Murine Gammaherpesvirus 68 Latency In Vivo.
| Title: | IKKα-Mediated Noncanonical NF-κB Signaling Is Required To Support Murine Gammaherpesvirus 68 Latency In Vivo. |
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| Authors: | Cieniewicz B; Department of Microbiology and Immunology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Molecular and Cellular Biology Program, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Kirillov V; Department of Microbiology and Immunology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Daher I; HIV and AIDS Malignancy Branch, National Cancer Institutegrid.48336.3a, Bethesda, Maryland, USA.; Li X; HIV and AIDS Malignancy Branch, National Cancer Institutegrid.48336.3a, Bethesda, Maryland, USA.; Oldenburg DG; Gundersen Medical Foundation, La Crosse, Wisconsin, USA.; Dong Q; Department of Microbiology and Immunology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Molecular and Cellular Biology Program, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Bettke JA; Molecular and Cellular Biology Program, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Marcu KB; Department of Biochemistry and Cell Biology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Department of Pathology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; Krug LT; Department of Microbiology and Immunology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.; HIV and AIDS Malignancy Branch, National Cancer Institutegrid.48336.3a, Bethesda, Maryland, USA. |
| Source: | Journal of virology [J Virol] 2022 May 25; Vol. 96 (10), pp. e0002722. Date of Electronic Publication: 2022 Apr 28. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Society For Microbiology; Original Publication: Baltimore, American Society for Microbiology. |
| MeSH Terms: | Herpesviridae Infections*/metabolism ; I-kappa B Kinase*/genetics ; I-kappa B Kinase*/metabolism ; NF-kappa B*/genetics ; NF-kappa B*/metabolism ; Rhadinovirus*/physiology ; Virus Latency*/genetics; Animals ; Mice ; Signal Transduction |
| Abstract: | Noncanonical NF-κB signaling is activated in B cells via the tumor necrosis factor (TNF) receptor superfamily members CD40, lymphotoxin β receptor (LTβR), and B-cell-activating factor receptor (BAFF-R). The noncanonical pathway is required at multiple stages of B cell maturation and differentiation, including the germinal center reaction. However, the role of this pathway in gammaherpesvirus latency is not well understood. Murine gammaherpesvirus 68 (MHV68) is a genetically tractable system used to define pathogenic determinants. Mice lacking the BAFF-R exhibit defects in splenic follicle formation and are greatly reduced for MHV68 latency. We report a novel approach to disrupt noncanonical NF-κB signaling exclusively in cells infected with MHV68. We engineered a recombinant virus that expresses a dominant negative form of IκB kinase α (IKKα), named IKKα-SA, with S176A and S180A mutations that prevent phosphorylation by NF-κB-inducing kinase (NIK). We controlled for the transgene insertion by introducing two all-frame stop codons into the IKKα-SA gene. The IKKα-SA mutant but not the IKKα-SA.STOP control virus impaired LTβR-mediated activation of NF-κB p52 upon fibroblast infection. IKKα-SA expression did not impact replication in primary fibroblasts or in the lungs of mice following intranasal inoculation. However, the IKKα-SA mutant was severely defective in the colonization of the spleen and in the establishment of latency compared to the IKKα-SA.STOP control and wild-type (WT) MHV68 at 16 days postinfection (dpi). Reactivation was undetectable in splenocytes infected with the IKKα-SA mutant, but reactivation in peritoneal cells was not impacted by IKKα-SA. Taken together, the noncanonical NF-κB signaling pathway is essential for the establishment of latency in the secondary lymphoid organs of mice infected with the murine gammaherpesvirus pathogen MHV68. IMPORTANCE The latency programs of the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with B cell lymphomas. It is critical to understand the signaling pathways that are used by gammaherpesviruses to establish and maintain latency in primary B cells. We used a novel approach to block noncanonical NF-κB signaling only in the infected cells of mice. We generated a recombinant virus that expresses a dominant negative mutant of IKKα that is nonresponsive to upstream activation. Latency was reduced in a route- and cell type-dependent manner in mice infected with this recombinant virus. These findings identify a significant role for the noncanonical NF-κB signaling pathway that might provide a novel target to prevent latent infection of B cells with oncogenic gammaherpesviruses. |
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| Grant Information: | T32 AI007539 United States AI NIAID NIH HHS; T32AI007539 HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) |
| Contributed Indexing: | Keywords: IKKα; gammaherpesvirus; latency; lytic replication; noncanonical NF-κB signaling; viral pathogenesis; virus-host interactions |
| Substance Nomenclature: | 0 (NF-kappa B); EC 2.7.11.10 (I-kappa B Kinase) |
| Entry Date(s): | Date Created: 20220428 Date Completed: 20220527 Latest Revision: 20240923 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9131860 |
| DOI: | 10.1128/jvi.00027-22 |
| PMID: | 35481781 |
| Database: | MEDLINE |
Journal Article