NF-kappaB p50 plays distinct roles in the establishment and control of murine gammaherpesvirus 68 latency.
NF-kappaB signaling is critical to the survival and transformation of cells infected by the human gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Here we have examined how elimination of the NF-kappaB transcription factor p50 from mice affects the life cycle of murine gammaherpesvirus 68 (MHV68). Notably, mice lacking p50 in every cell type were unable to establish a sufficiently robust immune response to control MHV68 infection, leading to high levels of latently infected B cells detected in the spleen and persistent virus replication in the lungs. The latter correlated with very low levels of virus-specific immunoglobulin G (IgG) in the infected p50(-/-) mice at day 48 postinfection. Because the confounding impact of the loss of p50 on the host response to MHV68 infection prevented a direct analysis of the role of this NF-kappaB family member on MHV68 latency in B cells, we generated and infected mixed p50(+/+)/p50(-/-) bone marrow chimeric mice. We show that the chimeric mice were able to control acute virus replication and exhibited normal levels of virus-specific IgG at 3 months postinfection, indicating the induction of a normal host immune response to MHV68 infection. However, in p50(+/+)/p50(-/-) chimeric mice the p50(-/-) B cells exhibited a significant defect compared to p50(+/+) B cells in supporting MHV68 latency. In addition to identifying a role for p50 in the establishment of latency, we determined that the absence of p50 in a subset of the hematopoietic compartment led to persistent virus replication in the lungs of the chimeric mice, providing evidence that p50 is required for controlling virus reactivation. Taken together, these data demonstrate that p50 is required for immune control by the host and has distinct tissue-dependent roles in the regulation of murine gammaherpesvirus latency during chronic infection.
Krug
Laurie T
LT
Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine, 1462 Clifton Road, Suite 429, Atlanta, GA 30322, USA. sspeck@emory.edu
Collins
Christopher M
CM
Gargano
Lisa M
LM
Speck
Samuel H
SH
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D007074:Immunoglobulin G / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000276:immunology / Q000378:metabolism*; D018144:Rhadinovirus / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000821:virology; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology; D010948:Viral Plaque Assay; D017735:Virus Latency
D007074:Immunoglobulin G; D052002:NF-kappa B p50 Subunit