Cytomegalovirus Inhibition of Extrinsic Apoptosis Determines Fitness and Resistance to Cytotoxic CD8 T Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 May 24

PMID 32444487

Citations 21

Authors

M Zeeshan Chaudhry

Rosaely Casalegno-Garduno

Katarzyna M Sitnik

Bahram Kasmapour

Ann-Kathrin Pulm

Ilija Brizic

Britta Eiz-Vesper

Andreas Moosmann

Stipan Jonjic

Edward S Mocarski

Luka Cicin-Sain

Affiliations

Soon will be listed here.

Abstract

Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.

Citing Articles

Cytomegalovirus Biology Viewed Through a Cell Death Suppression Lens.

Mocarski E Viruses. 2025; 16(12.

PMID: 39772130 PMC: 11680106. DOI: 10.3390/v16121820.

A Better Understanding of the Clinical and Pathological Changes in Viral Retinitis: Steps to Improve Visual Outcomes.

Nguyen N, Conrady C Microorganisms. 2025; 12(12.

PMID: 39770716 PMC: 11678148. DOI: 10.3390/microorganisms12122513.

Targeting nucleus pulposus cell death in the treatment of intervertebral disc degeneration.

Sun H, Guo J, Xiong Z, Zhuang Y, Ning X, Liu M JOR Spine. 2024; 7(4):e70011.

PMID: 39703198 PMC: 11655182. DOI: 10.1002/jsp2.70011.

Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection.

Gaspar Z, Szabo B, Cegledi A, Lakatos B Geroscience. 2024; 47(1):167-187.

PMID: 39207648 PMC: 11872864. DOI: 10.1007/s11357-024-01323-9.

No Time to Die: How Cytomegaloviruses Suppress Apoptosis, Necroptosis, and Pyroptosis.

Deng Y, Agueda-Pinto A, Brune W Viruses. 2024; 16(8).

PMID: 39205246 PMC: 11359067. DOI: 10.3390/v16081272.

References

Schub A, Schuster I, Hammerschmidt W, Moosmann A . CMV-specific TCR-transgenic T cells for immunotherapy. J Immunol. 2009; 183(10):6819-30. DOI: 10.4049/jimmunol.0902233. View

Adrain C, Murphy B, Martin S . Molecular ordering of the caspase activation cascade initiated by the cytotoxic T lymphocyte/natural killer (CTL/NK) protease granzyme B. J Biol Chem. 2004; 280(6):4663-73. DOI: 10.1074/jbc.M410915200. View

Krmpotic A, Messerle M, Crnkovic-Mertens I, Polic B, Jonjic S, Koszinowski U . The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo. J Exp Med. 1999; 190(9):1285-96. PMC: 2195686. DOI: 10.1084/jem.190.9.1285. View

Meiraz A, Garber O, Harari S, Hassin D, Berke G . Switch from perforin-expressing to perforin-deficient CD8(+) T cells accounts for two distinct types of effector cytotoxic T lymphocytes in vivo. Immunology. 2009; 128(1):69-82. PMC: 2747140. DOI: 10.1111/j.1365-2567.2009.03072.x. View

Kasmapour B, Kubsch T, Rand U, Eiz-Vesper B, Messerle M, Vondran F . Myeloid Dendritic Cells Repress Human Cytomegalovirus Gene Expression and Spread by Releasing Interferon-Unrelated Soluble Antiviral Factors. J Virol. 2017; 92(1). PMC: 5730771. DOI: 10.1128/JVI.01138-17. View

Ameres S, Besold K, Plachter B, Moosmann A . CD8 T cell-evasive functions of human cytomegalovirus display pervasive MHC allele specificity, complementarity, and cooperativity. J Immunol. 2014; 192(12):5894-905. DOI: 10.4049/jimmunol.1302281. View

Quinnan Jr G, Kirmani N, Rook A, Manischewitz J, Jackson L, Moreschi G . Cytotoxic t cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N Engl J Med. 1982; 307(1):7-13. DOI: 10.1056/NEJM198207013070102. View

Lu X, Pinto A, Kelly A, Cho K, Hill A . Murine cytomegalovirus interference with antigen presentation contributes to the inability of CD8 T cells to control virus in the salivary gland. J Virol. 2006; 80(8):4200-2. PMC: 1440476. DOI: 10.1128/JVI.80.8.4200-4202.2006. View

Proff J, Walterskirchen C, Brey C, Geyeregger R, Full F, Ensser A . Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner. Front Microbiol. 2016; 7:844. PMC: 4899442. DOI: 10.3389/fmicb.2016.00844. View

10.

Cicin-Sain L, Ruzsics Z, Podlech J, Bubic I, Menard C, Jonjic S . Dominant-negative FADD rescues the in vivo fitness of a cytomegalovirus lacking an antiapoptotic viral gene. J Virol. 2007; 82(5):2056-64. PMC: 2258921. DOI: 10.1128/JVI.01803-07. View

11.

Cicin-Sain L, Podlech J, Messerle M, Reddehase M, Koszinowski U . Frequent coinfection of cells explains functional in vivo complementation between cytomegalovirus variants in the multiply infected host. J Virol. 2005; 79(15):9492-502. PMC: 1181553. DOI: 10.1128/JVI.79.15.9492-9502.2005. View

12.

Brune W, Andoniou C . Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus. Viruses. 2017; 9(9). PMC: 5618015. DOI: 10.3390/v9090249. View

13.

Tischer B, Smith G, Osterrieder N . En passant mutagenesis: a two step markerless red recombination system. Methods Mol Biol. 2010; 634:421-30. DOI: 10.1007/978-1-60761-652-8_30. View

14.

Hengel H, Reusch U, Geginat G, Holtappels R, Ruppert T, Hellebrand E . Macrophages escape inhibition of major histocompatibility complex class I-dependent antigen presentation by cytomegalovirus. J Virol. 2000; 74(17):7861-8. PMC: 112316. DOI: 10.1128/jvi.74.17.7861-7868.2000. View

15.

Medema J, Toes R, Scaffidi C, Zheng T, Flavell R, Melief C . Cleavage of FLICE (caspase-8) by granzyme B during cytotoxic T lymphocyte-induced apoptosis. Eur J Immunol. 1998; 27(12):3492-8. DOI: 10.1002/eji.1830271250. View

16.

Dekhtiarenko I, Cicin-Sain L, Messerle M . Use of recombinant approaches to construct human cytomegalovirus mutants. Methods Mol Biol. 2014; 1119:59-79. DOI: 10.1007/978-1-62703-788-4_5. View

17.

Marquardt A, Halle S, Seckert C, Lemmermann N, Veres T, Braun A . Single cell detection of latent cytomegalovirus reactivation in host tissue. J Gen Virol. 2011; 92(Pt 6):1279-1291. DOI: 10.1099/vir.0.029827-0. View

18.

Ziegler H, Thale R, Lucin P, Muranyi W, Flohr T, Hengel H . A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartments. Immunity. 1997; 6(1):57-66. DOI: 10.1016/s1074-7613(00)80242-3. View

19.

Hutchinson S, Sims S, OHara G, Silk J, Gileadi U, Cerundolo V . A dominant role for the immunoproteasome in CD8+ T cell responses to murine cytomegalovirus. PLoS One. 2011; 6(2):e14646. PMC: 3033404. DOI: 10.1371/journal.pone.0014646. View

20.

Gold M, Munks M, Wagner M, McMahon C, Kelly A, Kavanagh D . Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. J Immunol. 2004; 172(11):6944-53. DOI: 10.4049/jimmunol.172.11.6944. View