NK cell interplay with cytomegaloviruses

Lisnić, Berislav; Lisnić, Vanda Juranić; Jonjić, Stipan

doi:10.1016/j.coviro.2015.07.001

Cited by 50 publications

(53 citation statements)

References 84 publications

(86 reference statements)

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“…sis, and various rare diseases (10,(46)(47)(48). We have explored the importance of heparanase production by NK cells in their infiltration into Matrigel and tumors, but it might be interesting to assess the impact of heparanase loss in other NK cell-dependent conditions such as Herpes virus infections or recruitment into inflammatory sites caused by TLR agonists or similar danger signals, in which NK cells are known to be critical in host defense (49,50). However, heparanase is best known for its involvement in tumor growth and angiogenesis, metastasis, and chemoresistance (10,46), indicating that heparanase is a promising therapeutic target for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

NK cell heparanase controls tumor invasion and immune surveillance

Putz

Mayfosh

Kos

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

NK cell heparanase controls tumor invasion and immune surveillance

Putz

Mayfosh

Kos

et al. 2017

Journal of Clinical Investigation

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“…Exquisite manipulation and targeting of cellular checkpoints have been hallmarks of the specific adaptation of herpesviruses to their hosts. The betaherpesvirus cytomegalovirus (CMV) encodes within its large 230 kilobases genome numerous proteins involved in the evasion of cellular innate and adaptive immune responses [1–3]. Additionally, CMV has been shown to antagonize the production of signaling molecules such as type I interferons (IFN) and proinflammatory cytokines, which are amongst the first messengers of an incoming viral attack [4].…”

Section: Introductionmentioning

confidence: 99%

The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription

et al. 2017

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The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.

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“…Thus, some viruses are able to expand activity and number of Treg cells as a mechanism to escape from an effective immune response [11–13]. This has been suggested also for cytomegalovirus (CMV) which is well known for developing different immune evasion strategies aimed at avoiding immune cell recognition [14, 15]. The support for this idea came from several previous studies, which demonstrated that murine cytomegalovirus (MCMV) infection induces both nTreg and iTreg cells [16–18].…”

Section: Introductionmentioning

confidence: 99%

IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection

et al. 2017

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Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection.

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NK cell interplay with cytomegaloviruses

Cited by 50 publications

References 84 publications

NK cell heparanase controls tumor invasion and immune surveillance

NK cell heparanase controls tumor invasion and immune surveillance

The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription

IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection

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