scholarly journals Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes

2016 ◽  
Vol 90 (8) ◽  
pp. 3819-3827 ◽  
Author(s):  
Selmir Avdic ◽  
Brian P. McSharry ◽  
Megan Steain ◽  
Emma Poole ◽  
John Sinclair ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Feedback Loop ◽  
Interleukin 10 ◽  
Negative Regulator ◽  
Viral Gene ◽  
Heme Oxygenase 1 ◽  
Solid Organ ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe human cytomegalovirus (HCMV) gene UL111A encodes cytomegalovirus-encoded human interleukin-10 (cmvIL-10), a homolog of the potent immunomodulatory cytokine human interleukin 10 (hIL-10). This viral homolog exhibits a range of immunomodulatory functions, including suppression of proinflammatory cytokine production and dendritic cell (DC) maturation, as well as inhibition of major histocompatibility complex (MHC) class I and class II. Here, we present data showing that cmvIL-10 upregulates hIL-10, and we identify CD14+monocytes and monocyte-derived macrophages and DCs as major sources of hIL-10 secretion in response to cmvIL-10. Monocyte activation was not a prerequisite for cmvIL-10-mediated upregulation of hIL-10, which was dose dependent and controlled at the transcriptional level. Furthermore, cmvIL-10 upregulated expression of tumor progression locus 2 (TPL2), which is a regulator of the positive hIL-10 feedback loop, whereas expression of a negative regulator of the hIL-10 feedback loop, dual-specificity phosphatase 1 (DUSP1), remained unchanged. Engagement of the hIL-10 receptor (hIL-10R) by cmvIL-10 led to upregulation of heme oxygenase 1 (HO-1), an enzyme linked with suppression of inflammatory responses, and this upregulation was required for cmvIL-10-mediated upregulation of hIL-10. We also demonstrate an important role for both phosphatidylinositol 3-kinase (PI3K) and STAT3 in the upregulation of HO-1 and hIL-10 by cmvIL-10. In addition to upregulating hIL-10, cmvIL-10 could exert a direct immunomodulatory function, as demonstrated by its capacity to upregulate expression of cell surface CD163 when hIL-10 was neutralized. This study identifies a mechanistic basis for cmvIL-10 function, including the capacity of this viral cytokine to potentially amplify its immunosuppressive impact by upregulating hIL-10 expression.IMPORTANCEHuman cytomegalovirus (HCMV) is a large, double-stranded DNA virus that causes significant human disease, particularly in the congenital setting and in solid-organ and hematopoietic stem cell transplant patients. A prominent feature of HCMV is the wide range of viral gene products that it encodes which function to modulate host defenses. One of these is cmvIL-10, which is a homolog of the potent immunomodulatory cytokine human interleukin 10 (hIL-10). In this study, we report that, in addition to exerting a direct biological impact, cmvIL-10 upregulates the expression of hIL-10 by primary blood-derived monocytes and that it does so by modulating existing cellular pathways. This capacity of cmvIL-10 to upregulate hIL-10 represents a mechanism by which HCMV may amplify its immunomodulatory impact during infection.

Novel Evidence That Hematopoietic-Specific PLC-β2 Is Required for Normal Homing and Engraftment of Hematopoietic Stem Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3342-3342
Author(s):  
Mateusz Adamiak ◽  
Ahmed Abdelbaset Ismail ◽  
Ahmed Abdel-Latif ◽  
Janina Ratajczak ◽  
Magdalena Kucia ◽  
...  
Keyword(s):  
Cell Migration ◽  
Phospholipase C ◽  
Baseline Level ◽  
Calcium Release ◽  
Membrane Lipid ◽  
Negative Regulator ◽  
Heme Oxygenase 1 ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Baseline

Abstract Background . We recently identified phospholipase C-β2 (PLC-β2) as the first lipolytic enzyme known to be involved in the mobilization of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) (Leukemia 2016, 4:919-28). The phospholipase C (PLC) family of enzymes consists of 13 members in six subfamilies, including the PLC-δ (1, 3, 4), -β (1-4), -γ (1, 2), -ε, -ζ, and -η isoforms. PLC enzymes are associated with cell surface receptors that convert phosphatidyloinositol-4,5-biphosphate into two important second messengers, diacylglycerol (DAG) and inositol-1,4.5-triphosphate (IP3). Among these isoforms, PLC-β2 is somewhat unique in being a hematopoietic-specific enzyme. Moreover, PLC-β2, when released extracellularly from granulocytes and HSPCs upon stimulation, cleaves glycolipid glycosylphosphatidylinositol anchor (GPI-A) in cell membranes and thus disrupts the structure of membrane lipid rafts, which are important in the retention of HSPCs in BM niches. It is well known that the major BM-retention receptors for HSPCs, CXCR4 and VLA-4, are membrane lipid raft-associated receptors. What is important for the current study, while performing mobilization studies, we previously found that BM cells from these animals show somewhat reduced chemotaxis in response to several chemoattractants involved in BM homing. Aim of the Study. Based on this latter observation, we became interested in the potential role of PLC-β2 in regulating the migration of HSPCs, as this enzyme could be potentially involved in BM homing and engraftment of HSPCs after transplantation. We also explored the potential relationship between PLC-β2 and heme oxygenase 1 (HO-1), which is, as we recently demonstrated, a negative regulator of HSPC trafficking (Cell Transplant. 2016 epub). Materials and Methods . We performed i) homing, ii) short-term engraftment, and iii) long-term competitive engraftment studies in WT mice transplanted with BM cells derived from PLC-β2-/- mice and control (WT) animals. Chemotaxis and adhesion of PLC-β2-/- HSPCs was evaluated in Transwell dishes in response to SDF-1, S1P, C1P, and ATP. The expression of HO-1 was evaluated by real-time PCR and western blotting. Finally, both HSPCs and Gr-1+ cells were evaluated for release of Ca2+ upon stimulation by homing factors. Results . We report here for first time that, besides its role in the release of HSPCs from BM niches, PLC-β2 also regulates the migration of HSPCs in response to chemotactic gradients of BM homing factors, including stromal derived factor-1 (SDF-1), sphingosine-1 phosphate (S1P), ceramide-1 phosphate C1P, and adenosine triphosphate (ATP). Specifically, HSPCs from PLC-β2-KO mice show impaired homing and engraftment in vivo after transplantation into lethally irradiated mice. This decrease in migration of HSPCs can be explained by impaired calcium release and calcium signaling in cells from PLC-β2-KO mice and a high baseline level of HO-1, an enzyme that negatively regulates cell migration, in PLC-β2-KO mouse cells. Downregulation of HO-1 activity in HSPCs improved homing of PLC-β2-/- BM cells. Conclusions . PLC-β2 plays an important role in homing and engraftment of HSPCs. The decrease in migration of HSPCs in PLC-β2-KO mice can be explained by impaired calcium release and a high baseline level of HO-1, an enzyme that negatively regulates cell migration and our data provides evidence that downregulation of HO-1 activity in HSPCs by small molecular inhibitors could become a new strategy to improve homing and engraftment after transplantation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immune Correlates of Protection Against Human Cytomegalovirus Acquisition, Replication, and Disease

2020 ◽  
Vol 221 (Supplement_1) ◽  
pp. S45-S59 ◽  
Author(s):  
Cody S Nelson ◽  
Ilona Baraniak ◽  
Daniele Lilleri ◽  
Matthew B Reeves ◽  
Paul D Griffiths ◽  
...  
Keyword(s):  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Performance Outcomes ◽  
Solid Organ ◽  
Cell Transplant ◽  
End Points ◽  
Hematopoietic Stem ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Infant Birth

Abstract Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects and an etiology of significant morbidity and mortality in solid organ and hematopoietic stem cell transplant recipients. There is tremendous interest in developing a vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease, yet after nearly a half-century of research and development in this field we remain without such an intervention. Defining immune correlates of protection is a process that enables targeted vaccine/immunotherapeutic discovery and informed evaluation of clinical performance. Outcomes in the HCMV field have previously been measured against a variety of clinical end points, including virus acquisition, systemic replication, and progression to disease. Herein we review immune correlates of protection against each of these end points in turn, showing that control of HCMV likely depends on a combination of innate immune factors, antibodies, and T-cell responses. Furthermore, protective immune responses are heterogeneous, with no single immune parameter predicting protection against all clinical outcomes and stages of HCMV infection. A detailed understanding of protective immune responses for a given clinical end point will inform immunogen selection and guide preclinical and clinical evaluation of vaccines or immunotherapeutics to prevent HCMV-mediated congenital and transplant disease.

scholarly journals Restriction of Human Cytomegalovirus Infection by Galectin-9

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Emily A. Machala ◽  
Selmir Avdic ◽  
Lauren Stern ◽  
Dirk M. Zajonc ◽  
Chris A. Benedict ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Human Herpesvirus ◽  
Temperature Shift ◽  
Cell Types ◽  
Cellular Protein ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Systems ◽  
Wide Range

ABSTRACTHuman cytomegalovirus (HCMV) is a ubiquitous human herpesvirus. While HCMV infection is generally asymptomatic in the immunocompetent, it can have devastating consequences in those with compromised or underdeveloped immune systems, including transplant recipients and neonates. Galectins are a widely expressed protein family that have been demonstrated to modulate both antiviral immunity and regulate direct host-virus interactions. The potential for galectins to directly modulate HCMV infection has not previously been studied, and our results reveal that galectin-9 (Gal-9) can potently inhibit HCMV infection. Gal-9-mediated inhibition of HCMV was dependent upon its carbohydrate recognition domains and thus dependent on glycan interactions. Temperature shift studies revealed that Gal-9 specific inhibition was mediated primarily at the level of virus-cell fusion and not binding. Additionally, we found that during reactivation of HCMV in hematopoietic stem cell transplant (HSCT) patients soluble Gal-9 is upregulated. This study provides the first evidence for Gal-9 functioning as a potent antiviral defense effector molecule against HCMV infection and identifies it as a potential clinical candidate to restrict HCMV infections.IMPORTANCEHuman cytomegalovirus (HCMV) continues to cause serious and often life-threatening disease in those with impaired or underdeveloped immune systems. This virus is able to infect and replicate in a wide range of human cell types, which enables the virus to spread to other individuals in a number of settings. Current antiviral drugs are associated with a significant toxicity profile, and there is no vaccine; these factors highlight a need to identify additional targets for the development of anti-HCMV therapies. We demonstrate for the first time that secretion of a member of the galectin family of proteins, galectin-9 (Gal-9), is upregulated during natural HCMV-reactivated infection and that this soluble cellular protein possesses a potent capacity to block HCMV infection by inhibiting virus entry into the host cell. Our findings support the possibility of harnessing the antiviral properties of Gal-9 to prevent HCMV infection and disease.

scholarly journals Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timo W. M. De Groof ◽  
Elizabeth G. Elder ◽  
Eleanor Y. Lim ◽  
Raimond Heukers ◽  
Nick D. Bergkamp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Early Gene ◽  
Latent Reservoir ◽  
Solid Organ ◽  
Cell Transplant ◽  
Viral Receptor ◽  
Transplant Patients ◽  
Latently Infected ◽  
Infected Cells

AbstractLatent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.

scholarly journals Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

2013 ◽  
Vol 57 (4) ◽  
pp. 1888-1894 ◽  
Author(s):  
William W. Hope ◽  
Michael VanGuilder ◽  
J. Peter Donnelly ◽  
Nicole M. A. Blijlevens ◽  
Roger J. M. Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Multiple Model ◽  
Pharmacokinetic Variability ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

scholarly journals Acute Kidney Injury and CKD Associated with Hematopoietic Stem Cell Transplantation

2019 ◽  
Vol 15 (2) ◽  
pp. 289-297 ◽  
Author(s):  
Amanda DeMauro Renaghan ◽  
Edgar A. Jaimes ◽  
Jolanta Malyszko ◽  
Mark A. Perazella ◽  
Ben Sprangers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Thrombotic Microangiopathy ◽  
Kidney Injury ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Wide Range

Hematopoietic stem cell transplantation is a life-saving therapy for many patients with cancer, as well as patients with some nonmalignant hematologic disorders, such as aplastic anemia, sickle cell disease, and certain congenital immune deficiencies. Kidney injury directly associated with stem cell transplantation includes a wide range of structural and functional abnormalities, which may be vascular (hypertension, thrombotic microangiopathy), glomerular (albuminuria, nephrotic glomerulopathies), and/or tubulointerstitial. AKI occurs commonly after stem cell transplant, affecting 10%–73% of patients. The cause is often multifactorial and can include sepsis, nephrotoxic medications, marrow infusion syndrome, hepatic sinusoidal obstruction syndrome, thrombotic microangiopathy, infections, and graft versus host disease. The risk of post-transplant kidney injury varies depending on patient characteristics, type of transplant (allogeneic versus autologous), and choice of chemotherapeutic conditioning regimen (myeloablative versus nonmyeloablative). Importantly, AKI is associated with substantial morbidity, including the need for KRT in approximately 5% of patients and the development of CKD in up to 60% of transplant recipients. AKI has been associated universally with higher all-cause and nonrelapse mortality regardless of transplant type, and studies have consistently shown extremely high (>80%) mortality rates in those patients requiring acute dialysis. Accordingly, prevention, early recognition, and prompt treatment of kidney injury are essential to improving kidney and patient outcomes after hematopoietic stem cell transplantation, and for realizing the full potential of this therapy.

Sign in / Sign up

Export Citation Format

Share Document