Killer cell proteases can target viral immediate-early proteins to control human cytomegalovirus infection in a noncytotoxic manner.
Liling Shan, Shuang Li, Jan Meeldijk, Bernadet Blijenberg, Astrid Hendriks, Karlijn J W M van Boxtel, Sara P H van den Berg, Ian J Groves, Martin Potts, Adriana Svrlanska, Thomas Stamminger, Mark R Wills, Niels Bovenschen
Author Information
Liling Shan: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Shuang Li: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. ORCID
Jan Meeldijk: Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Bernadet Blijenberg: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Astrid Hendriks: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Karlijn J W M van Boxtel: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Sara P H van den Berg: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Ian J Groves: Department of Medicine, University of Cambridge, Cambridge, United Kingdom. ORCID
Martin Potts: Department of Medicine, University of Cambridge, Cambridge, United Kingdom. ORCID
Adriana Svrlanska: Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany. ORCID
Thomas Stamminger: Institute for Virology, Ulm University Medical Center, Ulm, Germany. ORCID
Mark R Wills: Department of Medicine, University of Cambridge, Cambridge, United Kingdom. ORCID
Niels Bovenschen: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. ORCID
Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital defects and can trigger devastating disease in immune-suppressed patients. Cytotoxic lymphocytes (CD8+ T cells and NK cells) control HCMV infection by releasing interferon-γ and five granzymes (GrA, GrB, GrH, GrK, GrM), which are believed to kill infected host cells through cleavage of intracellular death substrates. However, it has recently been demonstrated that the in vivo killing capacity of cytotoxic T cells is limited and multiple T cell hits are required to kill a single virus-infected cell. This raises the question whether cytotoxic lymphocytes can use granzymes to control HCMV infection in a noncytotoxic manner. Here, we demonstrate that (primary) cytotoxic lymphocytes can block HCMV dissemination independent of host cell death, and interferon-α/β/γ. Prior to killing, cytotoxic lymphocytes induce the degradation of viral immediate-early (IE) proteins IE1 and IE2 in HCMV-infected cells. Intriguingly, both IE1 and/or IE2 are directly proteolyzed by all human granzymes, with GrB and GrM being most efficient. GrB and GrM cleave IE1 after Asp398 and Leu414, respectively, likely resulting in IE1 aberrant cellular localization, IE1 instability, and functional impairment of IE1 to interfere with the JAK-STAT signaling pathway. Furthermore, GrB and GrM cleave IE2 after Asp184 and Leu173, respectively, resulting in IE2 aberrant cellular localization and functional abolishment of IE2 to transactivate the HCMV UL112 early promoter. Taken together, our data indicate that cytotoxic lymphocytes can also employ noncytotoxic ways to control HCMV infection, which may be explained by granzyme-mediated targeting of indispensable viral proteins during lytic infection.
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