Cytomegalovirus immune evasion of myeloid lineage cells

Brinkmann, Melanie M.; Dağ, Franziska; Hengel, Hartmut; Messerle, Martin; Kalinke, Ulrich; Čičin‐Šain, Luka

doi:10.1007/s00430-015-0403-4

Cited by 40 publications

(37 citation statements)

References 153 publications

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“…5), this implies that the IFN, which is released after virus entry into LSEC, controlled MCMV replication. This in stern contrast to our protocols based on the addition of IFN-␤ to MCMV-infected LSEC cultures, where IFN-␤ had to be added at least 8 h prior to infection in order to upregulate host genes that prevent MCMV infection (28,57). Taken together, these observations lead to the conclusion that additional factors released from mDC in the presence of infected LSEC are required to complement and/or synergize with the antiviral activity of IFN.…”

Section: Discussionmentioning

confidence: 86%

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

Holzki

Dağ

Dekhtiarenko

et al. 2015

J Virol

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Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus whose reactivation from latency is a major cause of morbidity and mortality in immunocompromised hosts. Mouse CMV (MCMV) is a well-established model virus to study virus-host interactions. We showed in this study that the CD8-independent antiviral function of myeloid dendritic cells (mDC) is biologically relevant for the inhibition of MCMV replication in vivo and in vitro. In vivo ablation of CD11c ؉ DC resulted in higher viral titers and increased susceptibility to MCMV infection in the first 3 days postinfection. We developed in vitro coculture systems in which we cocultivated MCMV-infected endothelial cells or fibroblasts with T cell subsets and/or dendritic cells. H uman cytomegalovirus (HCMV) is a betaherpesvirus which establishes a lifelong latent infection in immunocompetenthosts. Latent HCMV is present in the majority of people worldwide, but the primary infection is usually asymptomatic. The primary infection is well contained by the immune cells, such as natural killer (NK) cells and T cells, which also prevent viral reactivation from latency (1, 2).Their activation depends on cross talk with dendritic cells (DC) (3, 4), and this interaction plays an important role in CMV control (5-7). The direct effect of DC on viral replication remains, however, unclear.In immunocompromised hosts, like AIDS patients or people undergoing transplantation, the virus cannot be contained, and its reactivation from latency has been associated with severe disease (8). Therefore, to develop new therapeutic approaches against CMV disease, it is exceedingly important to understand the immune mechanisms that drive the virus into latency.Murine cytomegalovirus (MCMV) is a natural pathogen of the mouse. It shows numerous analogies in latency and reactivation to the human virus, and its genome displays substantial similarity to the HCMV one (9). Therefore, MCMV is a widely used model for CMV infection and immunity (10)(11)(12).During primary infection, MCMV infects various different cell types, such as macrophages and DC but also nonhematopoietic cells, including endothelial and epithelial cells (13). On the other hand, the establishment of latency appears to be restricted to certain cell types. Latent HCMV was found in blood monocytes and in progenitor cells of the myeloid lineage (14-19), whereas liver sinusoidal endothelial cells (LSEC) were shown to be a site of MCMV latency and reactivation (20, 21), although myeloid cells might also present a latent reservoir in the mouse (22, 23).

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Section: Discussionmentioning

confidence: 86%

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

Holzki

Dağ

Dekhtiarenko

et al. 2015

J Virol

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“…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%

“…Upon HCMV infection, the protein levels of the CDS interferon gamma inducible protein 16 (IFI16), as well as of the transcription factors IRF3 and NF-κB are steadily downregulated [41], indicating that viral proteins target these important determinants of CMV infection [4]. For example, HCMV pUL37x1 has been shown to antagonize signaling downstream of the RLR adaptor MAVS in HeLa cells [42] and more recently, HCMV UL83 was observed to interact with and impede oligomerization of IFI16 in the nucleus, leading to reduced IFN signaling in fibroblasts [43].…”

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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“…HCMV has multiple immune evasion strategies 37 , which may make the microenvironment around latently infected myeloid cells suppressive to T-cell function, potentially creating an environment permissive for mycobacterial growth 43, 44 . This may be through effects of HCMV on the systemic immune response, but also through local effects.…”

Section: Human Cytomegalovirus Infectionmentioning

confidence: 99%

The convergent epidemiology of tuberculosis and human cytomegalovirus infection

Cobelens¹,

Nagelkerke

Fletcher

2018

F1000Res

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Although several factors are known to increase the risk of tuberculosis, the occurrence of tuberculosis disease in an infected individual is difficult to predict. We hypothesize that active human cytomegalovirus infection due to recent infection, reinfection or reactivation plays an epidemiologically relevant role in the aetiology of tuberculosis by precipitating the progression from latent tuberculosis infection to disease. The most compelling support for this hypothesis comes from the striking similarity in age-sex distribution between the two infections, important because the age-sex pattern of tuberculosis disease progression has not been convincingly explained. Cytomegalovirus infection and tuberculosis have other overlapping risk factors, including poor socio-economic status, sexual contact, whole blood transfusion and solid organ transplantation. Although each of these overlaps could be explained by shared underlying risk factors, none of the epidemiological observations refute the hypothesis. If this interaction would play an epidemiologically important role, important opportunities would arise for novel approaches to controlling tuberculosis.

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Cytomegalovirus immune evasion of myeloid lineage cells

Cited by 40 publications

References 153 publications

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

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

The convergent epidemiology of tuberculosis and human cytomegalovirus infection

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