Cytomegalovirus (CMV, a b-herpesvirus) establishes a persistent infection that is endemic in humans and mice. CMV causes acute clinical disease only if immunity is nave or compromised, exemplifying how coevolution with its host over millennia has resulted in a largely non-pathogenic dtente. The nature of this dtente is dependent upon the many strategies that CMV uses to subvert detection by the immune system. TNF-related cytokines are key regulators of antiviral defenses, and we have shown that both mouse and human CMV (MCMV and HCMV) inhibit expression of the TNF-related apoptosis inducing ligand death-receptors (TRAIL-DR) via the M166 and UL141 viral proteins, respectively. Viral mutants lacking these proteins are highly sensitive to control by TRAIL-expressing innate immune cells during the early-phase of CMV infection. In contrast, if MCMV is unable to restrict TRAIL-DR signaling via M166, the duration of persistent replication is dramatically longer. This is likely due to an altered CD4 T cell response that is unable to resolve persistence within the normal time frame. Together, our past and new results place the TRAIL signaling system at a critical apex in regulating various phases of the immune response to persistent virus infection. This proposal will reveal the how this TNF-family cytokine regulates antiviral immune defenses, and will help to define their broader importance in regulating inflammation and cell death.

Public Health Relevance

Cytomegalovirus (CMV) is a herpesvirus that infects the majority of humans, causing serious disease if the immune system is immature or out of balance. CMV inhibits many immune signaling pathways, and we have identified viral proteins that block signaling by TRAIL, an important host immune molecule for fighting infection. The impact that CMV inhibition of TRAIL has on viral fitness, and how TRAIL regulates various aspects of CMV immunity, are the focus of this proposal.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Virology - B Study Section (VIRB)
Program Officer
Beisel, Christopher E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Jolla Institute for Immunology
La Jolla
United States
Zip Code
Seelige, Ruth; Saddawi-Konefka, Robert; Adams, Nicholas M et al. (2018) Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection. Sci Rep 8:13670
Picarda, Gaƫlle; Benedict, Chris A (2018) Cytomegalovirus: Shape-Shifting the Immune System. J Immunol 200:3881-3889
Delpoux, Arnaud; Michelini, Rodrigo Hess; Verma, Shilpi et al. (2018) Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells. J Exp Med 215:575-594
Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626
Dufour, Florent; Rattier, Thibault; Shirley, Sarah et al. (2017) N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death. Cell Death Differ 24:500-510
Jackson, Sarah E; Redeker, Anke; Arens, Ramon et al. (2017) CMV immune evasion and manipulation of the immune system with aging. Geroscience 39:273-291
Lio, Chan-Wang J; McDonald, Bryan; Takahashi, Mariko et al. (2016) cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection. J Virol 90:7789-97
Verma, Shilpi; Weiskopf, Daniela; Gupta, Ankan et al. (2016) Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection. J Virol 90:650-8
Haynes, LaTeira D; Verma, Shilpi; McDonald, Bryan et al. (2015) Cardif (MAVS) Regulates the Maturation of NK Cells. J Immunol 195:2157-67
Stacey, Maria A; Marsden, Morgan; Pham N, Tu Anh et al. (2014) Neutrophils recruited by IL-22 in peripheral tissues function as TRAIL-dependent antiviral effectors against MCMV. Cell Host Microbe 15:471-83

Showing the most recent 10 out of 13 publications