Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Streblow, Daniel N.; Dumortier, Jerome; Moses, Ashlee V.; Orloff, Susan L.; Nelson, Jay A.

doi:10.1007/978-3-540-77349-8_22

Cited by 99 publications

(115 citation statements)

References 54 publications

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“…HCMVinfected fibroblasts and ECs release >1000 proteins (i.e. the HCMV secretome) compared with mock-infected cells or herpes simplex virus type 1-infected cells (120,121). This includes laminins and >41 cytokines, chemokines and chemokine receptors that affect angiogenesis and wound healing (chemokines IL-6, osteoprotegerin, growth-regulated oncogene, C-C motif chemokine ligand [CCL] 3, CCL5, CCL7, CCL20, CXCL5, and CXCL16; receptors TNF receptors I and II and ICAM1; growth factors TGF-b1, hepatocyte growth factor and granulocyte macrophage (122) and VCAM1, which, in the early phase of infection, enhance transendothelial cell migration of inflammatory cells including monocytes, promoting angiogenesis by secretion of VEGF (120,123).…”

Section: Proangiogenic and Proliferative Effectsmentioning

confidence: 99%

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The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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Section: Proangiogenic and Proliferative Effectsmentioning

confidence: 99%

“…HCMV encodes CC and CXC chemokine homologs, which further stimulate cell proliferation, chemotaxis and angiogenesis (121,125,126). The effect on SMC proliferation and migration in human blood vessels is observed both in vitro and in vivo (127,128).…”

Section: Colony-stimulating Factor) Hcmv Infection Of Ecs Induces Exmentioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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“…It has been shown that HCMV infection of ECs increases inflammation at the endothelium, promoting monocyte recruitment and extravasation, and increasing vascular permeability (1,(20)(21)(22)(23)(24)(25). Further, proinflammatory signaling elicited by the infection of vascular ECs contributes to angiogenesis and vascular disease (8,26,27).…”

mentioning

confidence: 99%

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Bughio

Umashankar

Wilson

et al. 2015

J Virol

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Endothelial cells (ECs) are a critical target of viruses, and infection of the endothelium represents a defining point in viral pathogenesis. Human cytomegalovirus (HCMV), the prototypical betaherpesvirus, encodes proteins specialized for entry into ECs and delivery of the genome to the nuclei of ECs. Virus strains competent to enter ECs replicate with differing efficiencies, suggesting that the virus encodes genes for postentry tropism in ECs. We previously reported a specific requirement for the UL133/8 locus of HCMV for replication in ECs. The UL133/8 locus harbors four genes: UL133, UL135, UL136, and UL138. In this study, we find that while UL133 and UL138 are dispensable for replication in ECs, both UL135 and UL136 are important. These genes are not required for virus entry or the expression of viral genes. The phenotypes associated with disruption of either gene reflect phenotypes observed for the UL133/8 NULL virus, which lacks the entire UL133/8 locus, but are largely distinct from one another. Viruses lacking UL135 fail to properly envelop capsids in the cytoplasm, produce fewer dense bodies (DB) than the wild-type (WT) virus, and are unable to incorporate viral products into multivesicular bodies (MVB). Viruses lacking UL136 also fail to properly envelop virions and produce larger dense bodies than the WT virus. Our results indicate roles for the UL135 and UL136 proteins in commandeering host membrane-trafficking pathways for virus maturation. UL135 and UL136 represent the first HCMV genes crucial for early-to late-stage tropism in ECs. H uman cytomegalovirus (HCMV) is a ubiquitous herpesvirus with 50 to 99% seroprevalence in the global population. Like all herpesviruses, HCMV persists for the lifetime of the host by way of latent infection (1-3). The persistence of HCMV is asymptomatic in immunocompetent individuals and is characterized by states of subclinical reactivation from latency and low-level virus shedding (1). However, in immunocompromised hosts, HCMV causes significant morbidity and mortality. Of particular concern are stem cell and solid-organ transplant patients, HIV/AIDS patients, and cancer patients undergoing chemotherapy or radiation regimens (4, 5). Additionally, HCMV is the leading cause of infectious disease-related birth defects in the United States, affecting 1 in 150 children born in the United States and most commonly resulting in mild to severe hearing loss (6). While CMV infection of seronegative women during pregnancy poses the most significant risk for severe sequelae in infants (microcephaly, cerebral palsy, and severe hearing loss or cognitive deficits), as many as 75% of congenital infections occur in infants whose mothers were seropositive at the time of conception, indicating that these infections result from reinfection or reactivation (7). Finally, the persistence of HCMV is increasingly associated with age-related pathologies, even when overt clinical symptoms are absent. Agerelated pathologies include vascular disease, immune dysfunction, and frailty (8-13)...

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“…In addition, it has been associated with glioblastoma and other cancers (2), cardiovascular disease (3), and immune sensescence (4). Cytomegalovirus is named for the morphological changes -enlarged cells with nuclear and cytoplasmic inclusions-observed in cytomegalic inclusion disease (5).…”

mentioning

confidence: 99%

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

Sharon-Friling

Shenk

2014

Proc. Natl. Acad. Sci. U.S.A.

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The human cytomegalovirus immediate-early protein pUL37x1 induces the release of Ca 2+ stores from the endoplasmic reticulum into the cytosol. This release causes reorganization of the cellular actin cytoskeleton with concomitant cell rounding. Here we demonstrate that pUL37x1 activates Ca 2+ -dependent protein kinase Cα (PKCα). Both PKCα and Rho-associated protein kinases are required for actin reorganization and cell rounding; however, only PKCα is required for the efficient production of virus progeny, arguing that HCMV depends on the kinase for a second function. PKCα activation is also needed for the production of large (1-5 μm) cytoplasmic vesicles late after infection. The production of these vesicles is blocked by inhibition of fatty acid or phosphatidylinositol-3-phosphate biosynthesis, and the failure to produce vesicles is correlated with substantially reduced production of enveloped virus capsids. These results connect earlier work identifying a requirement for lipid synthesis with specific morphological changes, and support the argument that the PKCα-induced large vesicles are either required for the efficient production of mature virus particles or serve as a marker for the process.capsid envelopment | virion assembly | virus-induced membranes

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Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Cited by 99 publications

References 54 publications

The Cell Biology of Cytomegalovirus: Implications for Transplantation

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

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