Monocytes Latently Infected with Human Cytomegalovirus Evade Neutrophil Killing

Krishna, Benjamin A.; Williamson, James C; Aslam, Yusuf; Farahi, Neda; Wood, Alexander; Romashova, Veronika; Roche, Kate; Murphy, Eain A.; Chilvers, Edwin R.; Lehner, Paul J.; Poole, Emma

doi:10.1016/j.isci.2019.01.007

Cited by 37 publications

(43 citation statements)

References 83 publications

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“…We next assessed whether downregulation of IFI16 and MNDA occurs during long term maintenance of latency; long term downregulation of HLA-DR is already known to be important for latent carriage of HCMV 41 . We infected monocytes with HCMV that drives mCherry from GATA2 promoter, and maintains this marker for far longer during latency than SV40 promoter-driven tags 51 . At 10 and 14 d.p.i., IFI16 remained absent and MNDA remained partially downregulated in infected cells (Figure 5C).…”

Section: Resultsmentioning

confidence: 99%

“…TB40/E BAC4 IE2-eYFP has been described previously 49,50 . TB40/E BAC4 GATA2mCherry has been described previously 51 . TB40/E with deleted NF-κB sites in the MIEP at positions −94, −157, −262 and −413, and the revertant virus, were a kind gift from Jeffery Meier and Ming Li (University of Iowa, United States), and have been described previously 52 .…”

Section: Methodsmentioning

confidence: 99%

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Interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency

Krishna

Williamson

Lim

et al. 2019

Preprint

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12Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected 13 cell to optimise latent carriage and reactivation. This is achieved, in part, through the expression of 14 viral genes, including the G-protein coupled receptor US28. Here, we use an unbiased proteomic 15 screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes 16 are downregulated by US28. We validate that MHC Class II and two PYHIN proteins, MNDA and 17 IFI16, are downregulated during experimental latency in primary human CD14 + monocytes. We find 18 that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner, but 19 only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing 20 IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early 21 2 gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 22 during latency is advantageous for the virus. 23 Importance 24 Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50-100% of humans 25 worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals, but is a 26 serious cause of mortality and morbidity in the immunocompromised and in neonates. In particular, 27 reactivation of HCMV in the transplant setting is a major cause of transplant failure and related 28 disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide 29 insights into potential ways to target the latent viral reservoir in at-risk patient populations. 30 31 both host and viral factors 18 . One viral factor that suppresses MIEP activity is the G-protein coupled 46 receptor (GPCR) US28, a virally encoded chemokine receptor homologue, which is expressed de 47 novo during latency as well as being delivered to cells with the incoming virion 19-24 and this 48 incoming viral US28 is functional 25 . US28 modulates the signalling pathways of early myeloid cells; it 49 attenuates MAP kinases, NF-κB, and c-fos, whilst activating STAT3 and iNOS 21,23,25 . All of these 50 contribute to the repression of MIEP activity. This US28-mediated signalling is so critical to latency 51 that US28-deleted viruses, or the loss of G-protein coupling by the US28 mutant R129A, result in lytic 52 infection of undifferentiated myeloid cells 19,21,23,25 . Furthermore, when examined, these US28-53 mediated effects on cell signalling did not occur during lytic infection or in permissive cells 21 , 54 implying that US28 represses the MIEP during latency but does not impair reactivation following 55 cellular differentiation. This is reflective of the cell type-specific nature of US28-mediated signalling 56 21,26 . 57Since US28 can modulate all these pathways and control the MIEP, we hypothesised that US28 58 would also cause changes in host protein expression. Here, we perform a proteomic screen 59 comparing host cell protein abundance in myelomonocytic TH...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency

Krishna

Williamson

Lim

et al. 2019

Preprint

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“…Expression of US28 in infected HPCs reprograms the cells into immunosuppressive monocytes (Zhu et al, 2018). The reported effects of HCMV infection on monocytes include increased lifespan through induction of anti-apoptotic genes (Chan et al, 2010;Reeves et al, 2012;Collins-McMillen et al, 2015;Peppenelli et al, 2016), re-programming the cells to an M1 or M2-like macrophage phenotype (Smith et al, 2004;Chan et al, 2008Chan et al, , 2012Avdic et al, 2013;Stevenson et al, 2014), modulation of cell signaling pathways (Kew et al, 2017;Krishna et al, 2017) evasion of killing by neutrophils (Elder et al, 2019), and induction of an anergic-like state (Shnayder et al, 2020).…”

Section: Cellular Tropism and Viral Gene Expressionmentioning

confidence: 99%

Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response

Forte

Zhang

Thorp

et al. 2020

Front. Cell. Infect. Microbiol.

152

103

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CMV is an ancient herpesvirus that has co-evolved with its host over millions of years. The 236 kbp genome encodes at least 165 genes, four non-coding RNAs and 14 miRNAs. Of the protein-coding genes, 43-44 are core replication genes common to all herpesviruses, while ∼30 are unique to betaherpesviruses. Many CMV genes are involved in evading detection by the host immune response, and others have roles in cell tropism. CMV replicates systemically, and thus, has adapted to various biological niches within the host. Different biological niches may place competing demands on the virus, such that genes that are favorable in some contexts are unfavorable in others. The outcome of infection is dependent on the cell type. In fibroblasts, the virus replicates lytically to produce infectious virus. In other cell types, such as myeloid progenitor cells, there is an initial burst of lytic gene expression, which is subsequently silenced through epigenetic repression, leading to establishment of latency. Latently infected monocytes disseminate the virus to various organs. Latency is established through cell type specific mechanisms of transcriptional silencing. In contrast, reactivation is triggered through pathways activated by inflammation, infection, and injury that are common to many cell types, as well as differentiation of myeloid cells to dendritic cells. Thus, CMV has evolved a complex relationship with the host immune response, in which it exploits cell type specific mechanisms of gene regulation to establish latency and to disseminate infection systemically, and also uses the inflammatory response to infection as an early warning system which allows the virus to escape from situations in which its survival is threatened, either by cellular damage or infection of the host with another pathogen. Spontaneous reactivation induced by cellular aging/damage may explain why extensive expression of lytic genes has been observed in recent studies using highly sensitive transcriptome analyses of cells from latently infected individuals. Recent studies with animal models highlight the potential for harnessing the host immune response to blunt cellular injury induced by organ transplantation, and thus, prevent reactivation of CMV and its sequelae.

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“…144 In vitro experiments have also shown that human neutrophils do not kill latently HCMV-infected monocytes owing to a suppressed secretion of neutrophil chemoattractants (i.e., S100A8/A9) by infected monocytes themeselves. 145 However, in contrast to the supportive role of neutrophils toward CMV, an in vivo study conducted in a mouse model of primary MCMV infection reported instead that neutrophils exert TNF-related apoptosis-inducing ligand (TRAIL)-mediated anti-MCMV activity in infected tissues upon their CXCL-1-mediated recruitment. 146 Despite the accumulating findings regarding potential interactions between neutrophils and CMV, both in human and in mouse models, much remains to be defined and clarified.…”

Section: Cytomegalovirus (Cmv) Reactivationmentioning

confidence: 99%

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Tecchio

Cassatella

2020

Cell Mol Immunol

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Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT.

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Monocytes Latently Infected with Human Cytomegalovirus Evade Neutrophil Killing

Cited by 37 publications

References 83 publications

Interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency

Interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency

Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

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