Polymorphisms and features of cytomegalovirus UL144 and UL146 in congenitally infected neonates with hepatic involvement

Guo, Gangqiang; Zhang, Liang; Ye, Sisi; Hu, Yingying; Li, Baoqing; Sun, Xia; Mao, Chenchen; Xu, Jianfeng; Zhang, Lifang; Xue, Xiangyang

doi:10.1371/journal.pone.0171959

Cited by 6 publications

(9 citation statements)

References 48 publications

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“…We observed three genotype 5 strains and no genotype 6 strains in the case group (one in each sub-group of cCMV, SNHL-CMV, and both diagnoses), while two genotype 6 and no genotype 5 strains were observed in the control group, a difference that was not found to be significant. The 2.6% frequency (3/116) of genotype 5 and 6 strains found in neonates in our study did not differ from frequencies found in other studies, which were in the range from 0 to 4.5% [ 9 , 14 , 21 – 24 ]. This study is yet the largest among UL146 genotyping studies from neonates with cCMV [ 9 , 14 , 20 – 24 ] and, to our knowledge, the only one with an established control group for comparison of genotype prevalence between patients and the background population.…”

Section: Discussioncontrasting

confidence: 66%

“…Previous studies have tried to establish a link between UL146 genotypes and cCMV without finding a clear association [ 9 , 14 , 20 , 21 ]. In addition, three studies have investigated whether severe cCMV was linked to specific UL146 genotypes by comparing symptomatic to asymptomatic cCMV cases, but no association was found [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

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The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population

et al. 2021

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Background Congenital cytomegalovirus disease (cCMV) is common and can be fatal or cause severe sequelae. Circulating strains of cytomegalovirus carry a high number of variable or disrupted genes. One of these is UL146, a highly diverse gene with 14 distinct genotypes encoding a CXC-chemokine involved in viral dissemination. UL146 genotypes 5 and 6 lack the conserved ELR motif, potentially affecting strain virulence. Here, we investigate whether UL146 genotypes 5 and 6 were associated with congenital CMV infection. Methods Viral DNA was extracted and UL146 sequenced from 116 neonatal dried blood spots (DBS) stored in the Danish National Biobank since 1982 and linked to registered cCMV cases through a personal identifier. These sequences were compared to UL146 control sequences obtained from CMV DNA extracted from 83 urine samples from children with suspected bacterial urinary tract infections. Results Three non-ELR UL146 genotypes (5 and 6) were observed among the cases (2.6%) and two were observed among the controls (2.4%; P > 0.99). Additionally, no significant association with cCMV was found for the other 12 genotypes in a post-hoc analysis, although genotype 8 showed a tendency to be more frequent among cases with 12 observations against three (P = 0.10). All fourteen genotypes were found to have little intra-genotype variation. Viral load, gender, and sample age were not found to be associated with any particular UL146 genotype. Conclusions No particular UL146 genotype was associated with cCMV in this nationwide retrospective case-control study. Associations between CMV disease and disrupted or polymorph CMV genes among immunosuppressed people living with HIV/AIDS and transplant recipients should be investigated in future studies.

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Section: Discussioncontrasting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population

et al. 2021

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“…CRD1 shows greater variation in UL144-A and UL144-C but is better conserved in UL144-B than the Towne strain. 6 This finding could be a reason for the enhanced virulence of UL144-A and UL144-C.…”

Section: Discussionmentioning

confidence: 98%

“…This domain's activity may vary among polymorphisms, leading to a range of clinical symptoms and prognoses. [5][6][7] Genetic polymorphisms of all these genes can be used to classify CMV strains and may affect the infectivity or pathogenicity of CMV.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus Genotype and Virulence in Infants with Congenital Infection

Hu¹,

Jian-gang²,

Sun³

et al. 2021

Journal of Pediatric Infectious Diseases

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Objective Cytomegalovirus (CMV) virulence may depend on genetic variability in several regions of the genome. This study aimed to assess specific CMV genotypes' association with the severity of symptomatic congenital CMV disease at birth. Methods CMV glycoprotein B (gB), glycoprotein N (gN), glycoprotein H (gH), and UL144 strains were identified by nested polymerase chain reaction, restriction fragment length polymorphism, and heteroduplex mobility assay single-stranded conformation polymorphism in 50 infants infected congenitally and 25 asymptomatic infants. Results gN1 (p = 0.010) and UL144-B (p = 0.034) genotypes were associated, by logistic regression, with reduced risk of developing symptomatic congenital CMV infection. gN1 (p = 0.020) and gN3 (p = 0.022) genotypes were associated with reduced risk of severe symptomatic disease. Conversely, gB1 (p = 0.018) was the most virulent genotype and was associated with severe symptoms. Conclusion An association among gB1, gN1, gN3, and UL144-B genotypes of CMV and severity of congenital CMV disease might exist. gB, gN, and UL144 genotypes could be important virological markers of infant infection.

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“…Along with complete UL141 and UL142 gene loss in the P4, P14, and P15 strains, NGS analysis also revealed partial loss of UL144 and UL140. UL144 is a highly variable gene within clinical isolates (42,83,84), but to date no inhibitory function for UL144 on NK cells has been demonstrated (85). However, UL144 can activate NF-kB via TRAF-6 recruitment (86) and induce the expression of the chemotactic factor CCL22, which hampers migration of CCR4-expressing NK cells (87).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variability of Human Cytomegalovirus Clinical Isolates Correlates With Altered Expression of Natural Killer Cell-Activating Ligands and IFN-γ

et al. 2021

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Human cytomegalovirus (HCMV) infection often leads to systemic disease in immunodeficient patients and congenitally infected children. Despite its clinical significance, the exact mechanisms contributing to HCMV pathogenesis and clinical outcomes have yet to be determined. One of such mechanisms involves HCMV-mediated NK cell immune response, which favors viral immune evasion by hindering NK cell-mediated cytolysis. This process appears to be dependent on the extent of HCMV genetic variation as high levels of variability in viral genes involved in immune escape have an impact on viral pathogenesis. However, the link between viral genome variations and their functional effects has so far remained elusive. Thus, here we sought to determine whether inter-host genetic variability of HCMV influences its ability to modulate NK cell responses to infection. For this purpose, five HCMV clinical isolates from a previously characterized cohort of pediatric patients with confirmed HCMV congenital infection were evaluated by next-generation sequencing (NGS) for genetic polymorphisms, phylogenetic relationships, and multiple-strain infection. We report variable levels of genetic characteristics among the selected clinical strains, with moderate variations in genome regions associated with modulation of NK cell functions. Remarkably, we show that different HCMV clinical strains differentially modulate the expression of several ligands for the NK cell-activating receptors NKG2D, DNAM-1/CD226, and NKp30. Specifically, the DNAM-1/CD226 ligand PVR/CD155 appears to be predominantly upregulated by fast-replicating (“aggressive”) HCMV isolates. On the other hand, the NGK2D ligands ULBP2/5/6 are downregulated regardless of the strain used, while other NK cell ligands (i.e., MICA, MICB, ULBP3, Nectin-2/CD112, and B7-H6) are not significantly modulated. Furthermore, we show that IFN-γ; production by NK cells co-cultured with HCMV-infected fibroblasts is directly proportional to the aggressiveness of the HCMV clinical isolates employed. Interestingly, loss of NK cell-modulating genes directed against NK cell ligands appears to be a common feature among the “aggressive” HCMV strains, which also share several gene variants across their genomes. Overall, even though further studies based on a higher number of patients would offer a more definitive scenario, our findings provide novel mechanistic insights into the impact of HCMV genetic variability on NK cell-mediated immune responses.

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Polymorphisms and features of cytomegalovirus UL144 and UL146 in congenitally infected neonates with hepatic involvement

Cited by 6 publications

References 48 publications

The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population

The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population

Cytomegalovirus Genotype and Virulence in Infants with Congenital Infection

Genetic Variability of Human Cytomegalovirus Clinical Isolates Correlates With Altered Expression of Natural Killer Cell-Activating Ligands and IFN-γ

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