scholarly journals Pathophysiology of Hyperechogenic Bowel in Congenitally Human Cytomegalovirus Infected Fetuses

2020 ◽  
Vol 8 (5) ◽  
pp. 779
Author(s):  
Liliana Gabrielli ◽  
Maria P. Bonasoni ◽  
Angela Chiereghin ◽  
Giulia Piccirilli ◽  
Eva C. Borgatti ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Ganglion Cells ◽  
Congenital Infection ◽  
Exocrine Secretion ◽  
Contributory Factor ◽  
Ultrasound Finding ◽  
Cmv Infection ◽  
Cd 117 ◽  
Group 4 ◽  
B Cell Leukemia

Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 weeks of gestation with congenital CMV infection. Ultrasound findings showed 4 fetuses with HB and 4 without. As negative group, 4 fetuses without CMV infection and without HB were studied. Immunohistochemistry for CMV, lymphocytic infiltrate, B-cell leukemia/lymphoma-2 (bcl-2), CD-117, cystic fibrosis transmembrane regulator (CFTR) were performed. HB fetuses showed multiple and sequential CMV-positive ganglion cells of Auerbach’s myenteric plexus. In the ganglia, bcl-2 was weakly expressed representing a reduced neuronal functionality. CD-117 revealed a regular distribution of Cajal cells, the pacemakers of intestinal contractility. Pancreas showed normal CFTR staining, indicating a preserved exocrine secretion, thus unlikely a contributory factor in HB. In CMV-infected fetuses without HB, CMV-positive cells were scatteredly found in ganglion cells and bcl-2 was strongly expressed. Intestinal CD-117 and pancreatic CFTR expression were similar to fetuses with HB. In conclusion, fetal CMV infection of the bowel may lead to peristalsis impairment (paralytic ileus) due to intestinal plexus involvement, which at ultrasound appeared as HB.

scholarly journals Development of a Vaccine against Human Cytomegalovirus: Advances, Barriers, and Implications for the Clinical Practice

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 551
Author(s):  
Sara Scarpini ◽  
Francesca Morigi ◽  
Ludovica Betti ◽  
Arianna Dondi ◽  
Carlotta Biagi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Human Cytomegalovirus ◽  
Congenital Infection ◽  
Health Concern ◽  
Live Vaccines ◽  
Target Populations ◽  
Immune Correlates ◽  
Common Causes ◽  
The Status ◽  
Life Threatening

Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymptomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, unclear immune correlates for protection, low number of available animal models, and insufficient general awareness. Moreover, there is a need to determine which may be the best target populations for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines undergoing clinical trials and understand barriers limiting their development.

Early-life environment influencing susceptibility to cytomegalovirus infection: evidence from the Leiden Longevity Study and the Longitudinal Study of Aging Danish Twins

2011 ◽  
Vol 140 (5) ◽  
pp. 835-841 ◽  
Author(s):  
L. H. MORTENSEN ◽  
A. B. MAIER ◽  
P. E. SLAGBOM ◽  
G. PAWELEC ◽  
E. DERHOVANESSIAN ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Human Cytomegalovirus ◽  
Family Environment ◽  
Early Life ◽  
Cytomegalovirus Infection ◽  
Genetic Factors ◽  
The Elderly ◽  
Same Sex ◽  
Cmv Infection ◽  
Early Life Environment

SUMMARYHuman cytomegalovirus (CMV) is a common herpesvirus establishing lifelong persisting infection, which has been implicated in immunosenescence and mortality in the elderly. Little is known about how and when susceptibility to CMV infection is determined. We measured CMV seroprevalence in two genetically informative cohorts. From the Leiden Longevity Study (LLS) we selected long-lived sib-pairs (n=844) and their middle-aged offspring and the offspring's partners (n=1452). From the Longitudinal Study of Aging Danish Twins (LSADT) 604 (302 pairs) same-sex monozygotic (MZ) and dizygotic (DZ) twins aged 73–94 years were included (n=302 pairs). Offspring of the long-lived LLS participants had significantly lower seroprevalence of CMV compared to their partners (offspring: 42%vs. partners: 51%,P=0·003). Of 372 offspring living with a CMV-positive partner, only 58% were infected. The corresponding number for partners was 71% (P<0·001). In the LSADT, MZ and DZ twins had high and similar CMV-positive concordance rates (MZ: 90%vs. DZ: 88%,P=0·51) suggesting that shared family environment accounts for the similarity within twin pairs. Our findings suggest that susceptibility to CMV infection – even under continuous within-partnership exposure – appears to be more strongly influenced by early-life environment than by genetic factors and adult environment.

scholarly journals Human Cytomegalovirus UL144 Is Associated with Viremia and Infant Development Sequelae in Congenital Infection

2010 ◽  
Vol 48 (11) ◽  
pp. 3956-3962 ◽  
Author(s):  
A. Waters ◽  
J. Hassan ◽  
C. deGascun ◽  
G. Kissoon ◽  
S. Knowles ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Infant Development ◽  
Congenital Infection

scholarly journals Human Cytomegalovirus Replication and Infection-Induced Syncytia Formation in Labial, Foreskin, and Fetal Lung Fibroblasts

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2355
Author(s):  
Alexis Aguiar ◽  
Melissa Galinato ◽  
Maite’ Bradley Silva ◽  
Bryant Toth ◽  
Michael A. McVoy ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Cytomegalovirus ◽  
Fetal Lung ◽  
Lung Fibroblasts ◽  
Anatomical Site ◽  
Cmv Infection ◽  
Viral Spread ◽  
Syncytia Formation

Only a handful of cell types, including fibroblasts, epithelial, and endothelial cells, can support human cytomegalovirus (CMV) replication in vitro, in striking contrast to the situation in vivo. While the susceptibility of epithelial and endothelial cells to CMV infection is strongly modulated by their anatomical site of origin, multiple CMV strains have been successfully isolated and propagated on fibroblasts derived from different organs. As oral mucosal cells are likely involved in CMV acquisition, we sought to evaluate the ability of infant labial fibroblasts to support CMV replication, compared to that of commonly used foreskin and fetal lung fibroblasts. No differences were found in the proportion of cells initiating infection, or in the amounts of viral progeny produced after exposure to the fibroblast-adapted CMV strain AD169 or to the endothelial cell-adapted strain TB40/E. Syncytia formation was, however, significantly enhanced in infected labial and lung fibroblasts compared to foreskin-derived cells, and did not occur after infection with AD169. Together, these data indicate that fibroblast populations derived from different tissues are uniformly permissive to CMV infection but retain phenotypic differences of potential importance for infection-induced cell–cell fusion, and ensuing viral spread and pathogenesis in different organs.

scholarly journals Human Cytomegalovirus Genomes Sequenced Directly from Clinical Material: Variation, Multiple-Strain Infection, Recombination and Mutation

2018 ◽  
Author(s):  
Nicolás M. Suárez ◽  
Gavin S. Wilkie ◽  
Elias Hage ◽  
Salvatore Camiolo ◽  
Marylouisa Holton ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
High Throughput Sequencing ◽  
Clinical Pathology ◽  
Congenital Infection ◽  
Population Based ◽  
Single Strain ◽  
Natural Mutation ◽  
Future Population

ABSTRACTThe genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination and natural mutation. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analysed, in the process facilitating the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating diversity, (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination, (iii) mutants with non-functional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae, and (iv) intrahost diversity in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology and pathogenesis of HCMV.

scholarly journals Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection

2020 ◽  
Author(s):  
Matthew L. Goodwin ◽  
Helen S. Webster ◽  
Hsuan-Yuan Wang ◽  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Effector Cell ◽  
Natural Infection ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Domain Specificity ◽  
Cell Functions ◽  
The Impact

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection, and the leading nongenetic cause of sensorineural hearing loss (SNHL) in newborns globally. A gB subunit vaccine administered with adjuvent MF59 (gB/MF59) is the most efficacious tested to-date, achieving 50% efficacy in preventing infection of HCMV-seronegative mothers. We recently discovered that gB/MF59 vaccination elicited primarily non-neutralizing antibody responses, that HCMV strains acquired by vaccinees more often included strains with gB genotypes that are distinct from the vaccine antigen, and that protection against HCMV acquisition correlated with ability of vaccine-elicited antibodies to bind to membrane associated gB. Thus, we hypothesized that gB-specific non-neutralizing antibody binding breadth and function are dependent on their epitope and genotype specificity as well as their ability to interact with membrane-associated gB. Twenty-four gB-specific monoclonal antibodies (mAbs) isolated from naturally HCMV-infected individuals were mapped for gB domain specificity by binding antibody multiplex assay (BAMA) and for genotype preference binding to membrane-associated gB presented on transfected cells. We defined their non-neutralizing functions including antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC). The isolated gB-specific non-neutralizing mAbs were primarily specific for Domain II and linear antigenic domain 2 site 2 (AD2). We observed variability in mAb gB genotype binding preference, with increased binding to gB genotypes 2 and 4. Functional studies identified two gB-specific mAbs that facilitate ADCP and have binding specificities of AD2 and Domain II. This investigation provides novel understanding on the impact of gB domain specificity and antigenic variability on gB-specific non-neutralizing antibody responses.ImportanceHCMV is the most common congenital infection worldwide, but development of a successful vaccine remains elusive. gB-specific non-neutralizing mAbs, represent a distinct anti-HCMV Ab subset implicated in the protection against primary infection during numerous phase-II gB/MF59 vaccine trials. By studying non-neutralizing gB-specific mAbs from naturally infected individuals, this study provides novel characterization of binding site specificity, genotypic preference, and effector cell functions mediated by mAbs elicited in natural infection. We found that a panel of twenty-four gB-specific non-neutralizing mAbs bind across multiple regions of the gB protein, traditionally through to be targeted by neutralizing mAbs only, and bind differently to gB depending if the protein is soluble versus embedded in a membrane. This investigation provides novel insight into the gB-specific binding characteristics and effector cell functions mediated by non-neutralizing gB-specific mAbs elicited through natural infection, providing new endpoints for future vaccine development.

scholarly journals Human Cytomegalovirus Genomes Sequenced Directly From Clinical Material: Variation, Multiple-Strain Infection, Recombination, and Gene Loss

2019 ◽  
Vol 220 (5) ◽  
pp. 781-791 ◽  
Author(s):  
Nicolás M Suárez ◽  
Gavin S Wilkie ◽  
Elias Hage ◽  
Salvatore Camiolo ◽  
Marylouisa Holton ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
High Throughput Sequencing ◽  
Gene Loss ◽  
Clinical Pathology ◽  
Congenital Infection ◽  
Population Based ◽  
Single Strain ◽  
Future Population

AbstractThe genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination, and gene loss. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analyzed, in the process enabling the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating variation; (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination; (iii) mutants with nonfunctional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae; and (iv) intrahost variation in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology, and pathogenesis of HCMV.

scholarly journals TLR2 2258 G>A single nucleotide polymorphism and the risk of congenital infection with human cytomegalovirus

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Wioletta Wujcicka ◽  
Edyta Paradowska ◽  
Mirosława Studzińska ◽  
Jan Wilczyński ◽  
Dorota Nowakowska
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Human Cytomegalovirus ◽  
Congenital Infection ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide

scholarly journals In Vivo Competence of Murine Cytomegalovirus under the Control of the Human Cytomegalovirus Major Immediate-Early Enhancer in the Establishment of Latency and Reactivation

2008 ◽  
Vol 82 (20) ◽  
pp. 10302-10307 ◽  
Author(s):  
Montse Gustems ◽  
Andreas Busche ◽  
Martin Messerle ◽  
Peter Ghazal ◽  
Ana Angulo
Keyword(s):  
Animal Model ◽  
Mouse Model ◽  
Human Cytomegalovirus ◽  
Pivotal Role ◽  
Immediate Early ◽  
Murine Cytomegalovirus ◽  
Direct Test ◽  
Cmv Infection ◽  
Physiological Functions

ABSTRACT The human cytomegalovirus (HCMV) major immediate-early enhancer has been postulated to play a pivotal role in the control of latency and reactivation. However, the absence of an animal model has obstructed a direct test of this hypothesis. Here we report on the establishment of an in vivo, experimentally tractable system for quantitatively investigating physiological functions of the HCMV enhancer. Using a neonate BALB/c mouse model, we show that a chimeric murine CMV under the control of the HCMV enhancer is competent in vivo, replicating in key organs of mice with acute CMV infection and exhibiting latency/reactivation features comparable for the most part to those of the parental and revertant viruses.

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