Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling

Goodwin, Christopher M.; Ciesla, Jessica H.; Munger, Joshua

doi:10.3390/v10090447

Cited by 35 publications

(32 citation statements)

References 131 publications

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“…Furthermore, two fairly newly discovered HCMV miRNAs, miR-US5-1 and miR-UL112-3p, have recently been shown to target members of the IκB kinase (IKK) complex, IKKα and IKKβ, therefore reducing NF-κB signaling during late infection (Hancock et al, 2017) and, consequently, the expression of proinflammatory genes encoding cytokines and chemokines (Liu et al, 2017). The secretion of cytokines and chemokines including IL-6 is further inhibited by miR-UL148D, viral miRNA that has been shown to be predominantly expressed during latency (Lau et al, 2016;Goodwin et al, 2018).…”

Section: Microrna Signaling In Cytomegalovirus Infectionmentioning

confidence: 99%

MicroRNA Involvement in Signaling Pathways During Viral Infection

Barbu

Condrat

Thompson

et al. 2020

Front. Cell Dev. Biol.

119

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Section: Microrna Signaling In Cytomegalovirus Infectionmentioning

confidence: 99%

MicroRNA Involvement in Signaling Pathways During Viral Infection

Barbu

Condrat

Thompson

et al. 2020

Front. Cell Dev. Biol.

119

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“…There are three types of IFN: type I (α, β, κ, ω, τ , and ε), type II (γ), and type III (λ1, λ2, λ3, λ4). Type I and II IFNs are the best characterized in the context of HCMV and their induction, antiviral roles as well as the viral antagonism of these processes have been extensively reviewed (14)(15)(16)(17)(18)(19). A role for type III IFNs, in the innate response to HCMV and murine CMV (MCMV), whose pathogenesis closely parallels that of HCMV (20), has recently been elucidated (21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Interferon-Independent Innate Responses to Cytomegalovirus

et al. 2019

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The critical role of interferons (IFNs) in mediating the innate immune response to cytomegalovirus (CMV) infection is well established. However, in recent years the functional importance of the IFN-independent antiviral response has become clearer. IFN-independent, IFN regulatory factor 3 (IRF3)-dependent interferon-stimulated gene (ISG) regulation in the context of CMV infection was first documented 20 years ago. Since then several IFN-independent, IRF3-dependent ISGs have been characterized and found to be among the most influential in the innate response to CMV. These include virus inhibitory protein, endoplasmic reticulum-associated IFN-inducible (viperin), ISG15, members of the interferon inducible protein with tetratricopeptide repeats (IFIT) family, interferon-inducible transmembrane (IFITM) proteins and myxovirus resistance proteins A and B (MxA, MxB). IRF3-independent, IFN-independent activation of canonically IFN-dependent signaling pathways has also been documented, such as IFN-independent biphasic activation of signal transducer and activator of transcription 1 (STAT1) during infection of monocytes, differential roles of mitochondrial and peroxisomal mitochondrial antiviral-signaling protein (MAVS), and the ability of human CMV (HCMV) immediate early protein 1 (IE1) protein to reroute IL-6 signaling and activation of STAT1 and its associated ISGs. This review examines the role of identified IFN-independent ISGs in the antiviral response to CMV and describes pathways of IFN-independent innate immune response induction by CMV.

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“…Infection recognition was shown to occur very rapidly in monocytes and fibroblasts, leading to the activation of the transcription factors IRF3 and NF-κB, and to the implementation of the IFN transcriptional program within 4-8 hours [113, 114, 116, 118–122]. Structural components of the virion, such as the tegument proteins pp65 and/or pp71 [113, 114, 123, 124], as well as viral immediate-early and early proteins [125, 126] then cooperate to blunt these responses via multiple mechanisms, including inactivation of the double-stranded DNA sensor MB21D1/cGAS, blockage of the STING-TBK1-IRF3 complex assembly, inhibition of NF-kB binding to DNA, and degradation of the signal transduction molecules JAK1 and STAT2 [123, 124, 127–132]. IFN-related genes that are highly transcribed at 4-8 hours pi may thus be downregulated at 24 hours pi, or upon full implementation of viral countermeasures.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptome analysis of CD34⁺stem cell-derived myeloid cells identifies a CFU-GEMM-like population permissive to human cytomegalovirus infection

Galinato¹,

Shimoda²,

Aguiar³

et al. 2018

Preprint

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13 14 Short title: single-cell analysis of CMV-infected myeloid cells 2 15 ABSTRACT 16 Myeloid cells are important sites of lytic and latent infection by human cytomegalovirus (CMV). We 17 previously showed that only a small subset of myeloid cells differentiated from CD34 + hematopoietic 18 stem cells is permissive to CMV replication, underscoring the heterogeneous nature of these 19 populations. The exact identity of susceptible and resistant cell types, and the cellular features 20 characterizing permissive cells, however, could not be dissected using averaging transcriptional 21 analysis tools such as microarrays and, hence, remained enigmatic. Here, we profile the transcriptomes 22 of ~ 7000 individual cells at day one post-infection using the 10X genomics platform. We show that 23 viral transcripts are detectable in the majority of the cells, suggesting that virion entry is unlikely to be 24 the main target of cellular restriction mechanisms. We further show that viral replication occurs in a 25 small but specific sub-group of cells transcriptionally related to, and likely derived from, a cluster of 26 cells expressing markers of Colony Forming Unit -Granulocyte, Erythrocyte, Monocyte, 27 Megakaryocyte (CFU-GEMM) oligopotent progenitors. Compared to the remainder of the population, 28 CFU-GEMM cells are enriched in transcripts with functions in mitochondrial energy production, cell 29 proliferation, RNA processing and protein synthesis, and express similar or higher levels of interferon-30 related genes. While expression levels of the former are maintained in infected cells, the latter are 31 strongly down-regulated. We thus propose that the preferential infection of CFU-GEMM cells may be 32 due to the presence of a pre-established pro-viral environment, requiring minimal optimization efforts 33 from viral effectors, rather than to the absence of specific restriction factors. Together, these findings 34 identify a potentially new population of myeloid cells susceptible to CMV replication, and provide a 35 possible rationale for their preferential infection. 3 AUTHOR SUMMARY37 Myeloid cells such as monocytes and dendritic cells are critical targets of CMV infection. To identify 38 the cellular factors that confer susceptibility or resistance to infection, we profiled the transcriptomes of 39~ 7,000 single cells from a population of semi-permissive myeloid cells infected with CMV. We found 40 that viral RNAs are detectable in the majority of the cells, but that marked expression of CMV lytic 41 genes occurs in only a small subset of cells transcriptionally related to a cluster of CFU-GEMM 42 progenitors that express similar amounts of transcripts encoding interferon-related anti-viral factors as 43 the rest of the population but higher levels of transcripts encoding proteins required for energy, RNA, 44 and protein production. We thus conclude that the preferential infection of CFU-GEMM cells might be 45 due to the pre-existing presence of an intracellular environment conducive to infection onset, rather ...

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Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling

Cited by 35 publications

References 131 publications

MicroRNA Involvement in Signaling Pathways During Viral Infection

MicroRNA Involvement in Signaling Pathways During Viral Infection

Interferon-Independent Innate Responses to Cytomegalovirus

Single-cell transcriptome analysis of CD34⁺stem cell-derived myeloid cells identifies a CFU-GEMM-like population permissive to human cytomegalovirus infection

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Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling

Cited by 35 publications

References 131 publications

MicroRNA Involvement in Signaling Pathways During Viral Infection

MicroRNA Involvement in Signaling Pathways During Viral Infection

Interferon-Independent Innate Responses to Cytomegalovirus

Single-cell transcriptome analysis of CD34+stem cell-derived myeloid cells identifies a CFU-GEMM-like population permissive to human cytomegalovirus infection

Contact Info

Product

Resources

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Single-cell transcriptome analysis of CD34⁺stem cell-derived myeloid cells identifies a CFU-GEMM-like population permissive to human cytomegalovirus infection