Prevalence of Congenital Cytomegalovirus Infection Assessed Through Viral Genome Detection in Dried Blood Spots in Children with Autism Spectrum Disorders

Gentile, Ivan; Zappulo, Emanuela; Riccio, Maria Pia; Binda, Sandro; Bubba, Laura; Pellegrinelli, Laura; Scognamiglio, Domenico; Operto, Francesca Felicia; Margari, Lucia; Borgia, Guglielmo; Bravaccio, Carmela

doi:10.21873/invivo.11085

Cited by 23 publications

(18 citation statements)

References 68 publications

(67 reference statements)

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“…However, it is amongst pregnant women and newborns that HCMV has a disproportionate impact on public health [ 9 ]. Just over 1 in 200 infants born in the United States are congenitally infected with HCMV, and approximately a fifth of these infants will suffer life-long neurological complications [ 10 , 11 ], including hearing and vision loss, seizures, behavioral disorders, and developmental delays [ 12 – 15 ]. Ideally, infection during pregnancy would be avoided, but this is challenging.…”

Section: Introductionmentioning

confidence: 99%

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

et al. 2020

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A trimeric glycoprotein complex on the surface of human cytomegalovirus (HCMV) binds to platelet-derived growth factor (PDGF) receptor α (PDGFRα) to mediate host cell recognition and fusion of the viral and cellular membranes. Soluble PDGFRα potently neutralizes HCMV in tissue culture, and its potential use as an antiviral therapeutic has the benefit that any escape mutants will likely be attenuated. However, PDGFRα binds multiple PDGF ligands in the human body as part of developmental programs in embryogenesis and continuing through adulthood. Any therapies with soluble receptor therefore come with serious efficacy and safety concerns, especially for the treatment of congenital HCMV. Soluble virus receptors that are orthogonal to human biology might resolve these concerns. This engineering problem is solved by deep mutational scanning on the D2-D3 domains of PDGFRα to identify variants that maintain interactions with the HCMV glycoprotein trimer in the presence of competing PDGF ligands. Competition by PDGFs is conformation-dependent, whereas HCMV trimer binding is independent of proper D2-D3 conformation, and many mutations at the receptor-PDGF interface are suitable for functionally separating trimer from PDGF interactions. Purified soluble PDGFRα carrying a targeted mutation succeeded in displaying wild type affinity for HCMV trimer with a simultaneous loss of PDGF binding, and neutralizes trimer-only and trimer/pentamer-expressing HCMV strains infecting fibroblasts or epithelial cells. Overall, this work makes important progress in the realization of soluble HCMV receptors for clinical application.

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Section: Introductionmentioning

confidence: 99%

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

et al. 2020

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“…dysplasia of brain and neuron, and even death (3)(4)(5). Therefore, it is imperative to evaluate the severity of illness and efficacy on children and to implement effective treatments.…”

Section: Efficacy Of Small-dose Ganciclovir On Cytomegalovirus Infections In Children and Its Effects On Liver Function And Mir-ul112-3p mentioning

confidence: 99%

Efficacy of small‑dose ganciclovir on cytomegalovirus infections in children and its effects on liver function and miR‑UL112‑3p expression

et al. 2021

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The aim of the study was to explore the efficacy of small-dose ganciclovir on cytomegalovirus infections as well as its effects on the liver function and miR-UL112-3p of children. A total of 141 children infected with cytomegalovirus admitted to the Affiliated Hospital of Weifang Medical University from May 2015 to August 2017 were enrolled, of which 74 children were treated with small-dose ganciclovir as an observation group (Obs group), and the rest were treated with conventional-dose ganciclovir as a control group (Con group). The two groups were compared in efficacy after treatment, changes of liver function indexes [total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] and miR-UL112-3p before and after treatment, and adverse reactions after treatment. A receiver operating characteristic (ROC) curve was drawn to analyze the value of miR-UL112-3p in predicating efficacy on cytomegalovirus infections in children, and Pearson's correlation analysis was carried out to analyze the correlation between miR-UL112-3p expression and TB, ALT and AST. The MV-DNA level between the two groups after treatment was compared. The two groups showed no significant difference in efficacy and adverse reactions (both P>0.05), and before treatment, there was also no significant difference between the two groups in miR-UL112-3p, TB, ALT, and AST, while after treatment, both groups showed lower levels of miR-UL112-3p, TB, ALT, and AST, and the Obs group showed significantly lower levels thereof than the Con group (all P<0.05). In addition, the area under the curve (AUC), specificity, and sensitivity of miR-UL112-3p in the ROC curve of the Obs group were 0.866, 73.77 and 84.62%, respectively, while the AUC, specificity, and sensitivity of the ROC of the Con group were 0.837, 75.44, and 90.00%, respectively. Furthermore, miR-UL112-3p was positively correlated with TB, ALT, and AST, respectively. The CMV-DNA level in the Obs group was lower than that in the Con group, but the difference was not significant, and the level of CMV-DNA was positively correlated with that of miR-UL112-3p. In conclusion, small-dose ganciclovir can better improve the liver function of the children, and downregulate miR-UL112-3p in them. The AUC, specificity, and sensitivity of miR-UL112-3p for predicting the efficacy of small-dose ganciclovir were 0.866, 73.77 and 84.62%, respectively, and the AUC, specificity, and sensitivityfor predicting the efficacy of conventional-dose ganciclovir were 0.837, 75.44 and 90.00%, respectively.

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“…Moreover, the sensitivity of DBS for the retrospective diagnosis of cCMV has been clearly proved in children developing the related-illness in the first few years of life [31,32] and it is acknowledged that many serious health conditions -such as SNHL, vestibular disorders, abnormalities of cortical development, pachygyria, cholestasis [31][32][33][34] and autism spectrum disorder [35] -have benefited from a retrospective DBS analysis. The opportunity to carry out retrospective studies to find a causal relationship between congenital infections and pathological conditions of unknown or debated origin suffers from the length of storage time of residual DBS specimens.…”

Section: Main Textmentioning

confidence: 99%

Diagnosing congenital Cytomegalovirus infection: don’t get rid of dried blood spots

et al. 2020

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Background: Congenital Cytomegalovirus (cCMV) is a serious global public health issue that can cause irreversible fetal and neonatal congenital defects in symptomatic or asymptomatic newborns at birth. In absence of universal cCMV screening, the retrospective diagnosis of cCMV infection in children is only possible by examining Dried Blood Spot (DBS) samples routinely collected at birth and stored for different time spans depending on the newborn screening regulations in force in different countries. In this article, we summarize the arguments in favor of long-term DBS sample storage for detecting cCMV infection. Main text: CMV infection is the most common cause of congenital infection resulting in severe defects and anomalies that can be apparent at birth or develop in early childhood. Sensorineural hearing loss is the most frequent consequence of cCMV infection and may have a late onset and progress in the first years of life. The virological diagnosis of cCMV is essential for clinical research and public health practices. In fact, in order to assess the natural history of CMV infection and distinguish between congenital or acquired infection, children should be diagnosed early by analyzing biological samples collected in the first weeks of life (3 weeks by using viral culture and 2 weeks by molecular assays), which, unfortunately, are not always available for asymptomatic or mildly symptomatic children. It now seems possible to overcome this problem since the CMV-DNA present in the blood of congenitally infected newborns can be easily retrieved from the DBS samples on the Guthrie cards routinely collected and stored within 3 days from birth in the neonatal screening program for genetic and congenital diseases. Early collection and long-term storage are inexpensive methods for long-term bio-banking and are the key points of DBS testing for the detection of cCMV. Conclusion: DBS sampling is a reliable and inexpensive method for long-term bio-banking, which enables to diagnose known infectious diseases-including cCMV-as well as diseases not jet recognized, therefore their storage sites and long-term storage conditions and durations should be the subject of political decision-making.

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Prevalence of Congenital Cytomegalovirus Infection Assessed Through Viral Genome Detection in Dried Blood Spots in Children with Autism Spectrum Disorders

Cited by 23 publications

References 68 publications

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

Efficacy of small‑dose ganciclovir on cytomegalovirus infections in children and its effects on liver function and miR‑UL112‑3p expression

Diagnosing congenital Cytomegalovirus infection: don’t get rid of dried blood spots

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