Cytomegalovirus alpha-chemokine genotypes are associated with clinical manifestations in children with congenital or postnatal infections

Paradowska, Edyta; Jabłońska, Agnieszka; Płóciennikowska, Agnieszka; Studzińska, Mirosława; Suski, Patrycja; Wiśniewska-Ligier, Małgorzata; Dzierżanowska-Fangrat, Katarzyna; Kasztelewicz, Beata; Woźniakowska-Gęsicka, Teresa; Leśnikowski, Zbigniew J.

doi:10.1016/j.virol.2014.06.020

Cited by 12 publications

(18 citation statements)

References 45 publications

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“…Because of the small sample size and large number of genotypes for these genes, no specific UL146 or UL147 genotype was associated with disease outcome. In a study of 121 infants from Poland (32 of whom were congenitally-infected newborns), genotype G1 was more prevalent in symptomatic infants; and an association between UL146 genotype and viruria was identified (38). Nevertheless, much larger studies with hundreds of isolates will be required to identify a correlation between UL146/UL147 genotypes and outcome of congenital infection.…”

Section: Genetic Variability In Ul146 and Ul147mentioning

confidence: 99%

Strain Variation and Disease Severity in Congenital Cytomegalovirus Infection

Arav‐Boger

2015

Infectious Disease Clinics of North America

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Synopsis The wide spectrum of congenital CMV disease and known differences in the biology and in vitro growth of CMV strains continue to drive studies in search for specific viral genetic determinants that may predict severity of congenital CMV disease. Several CMV genes have been studied in detail in congenitally-infected children, but the complexity of the viral genome and differences in the definition of symptomatic disease vs. asymptomatic CMV infection continue to raise questions related to what constitutes a pathogenic CMV strain. In addition, the prevalence and role of multiple CMV strains as opposed to infection with a single strain in disease severity is debated. Although the new era of highly-sensitive next generation sequencing assays may provide detailed information on multiple genetic loci, strict criteria for differentiating between strains will be required. Identifying a viral marker (or combination of markers) for prediction of disease outcome could have a major impact on pre-natal diagnosis and vaccine development. Large, well-controlled studies with long-term follow-up and use of standardized high stringency molecular techniques will be required to move the field forward. Genetic variation of host genes may play an adjunctive role in the outcome of congenital CMV disease.

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Section: Genetic Variability In Ul146 and Ul147mentioning

confidence: 99%

Strain Variation and Disease Severity in Congenital Cytomegalovirus Infection

Arav‐Boger

2015

Infectious Disease Clinics of North America

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“…Why only some neonates infected with HCMV, but not all population, develop symptoms is unknown [ 5 ]. Although the host immune system is believed to largely determine the outcome of infection, sequence polymorphisms in the infecting strains are also thought to be associated with outcome and tissue tropism [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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

Guo

Zhang

et al. 2017

PLoS ONE

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Human cytomegalovirus is a significant agent of hepatic involvement in neonates. In this study, we investigated the polymorphisms and features of the viral genes UL144 and UL146 as well as their significance to congenital hepatic involvement. In 79 neonates with congenital cytomegalovirus infection and hepatic involvement, full length UL144 and UL146 were successfully amplified in 73.42% and 60.76% of cases, respectively. Sequencing indicated that both genes were hypervariable. Notably, UL144 genotype B was highly associated with aspartate aminotransferase (P = 0.028) and lactate dehydrogenase (P = 0.046). Similarly, UL146 genotype G1 and G13 were significantly associated with CMV IgM (P = 0.026), CMV IgG (P = 0.034), alanine aminotransferase (P = 0.019), and aspartate aminotransferase (P = 0.032). In conclusion, dominant UL144 (genotype B) and UL146 (genotype G1 and G13) genotypes are associated with elevated levels of enzymes and CMV IgM and IgG of cytomegalovirus infection.

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“…These findings have spiked the interest of clinical virologists in identifying potential correlations between genetic variants and the pathogenic potential of different isolates. Several studies have found some evidence to correlate specific genotypes with disease outcome, investigating polymorphisms in the UL55 (glycoprotein B) (16)(17)(18)(19), UL73 (glycoprotein N) (20)(21)(22), UL75 (glycoprotein H) (23), UL144 (tumor necrosis factor alpha [TNF-␣]-like receptor) (24)(25)(26), and UL146 and UL147 (viral CXCL chemokines) (27,28) genes. Others, however, found no evidence of these relationships (29)(30)(31)(32).…”

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confidence: 99%

High-Throughput Analysis of Human Cytomegalovirus Genome Diversity Highlights the Widespread Occurrence of Gene-Disrupting Mutations and Pervasive Recombination

Sijmons

Thys

Ngwese

et al. 2015

J Virol

155

219

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Human cytomegalovirus is a widespread pathogen of major medical importance. It causes significant morbidity and mortality in immunocompromised individuals, and congenital infections can result in severe disabilities or stillbirth. Development of a vaccine is prioritized, but no candidate is close to release. Although correlations of viral genetic variability with pathogenicity are suspected, knowledge about the strain diversity of the 235-kb genome is still limited. In this study, 96 full-length human cytomegalovirus genomes from clinical isolates were characterized, quadrupling the amount of information available for full-genome analysis. These data provide the first high-resolution map of human cytomegalovirus interhost diversity and evolution. We show that cytomegalovirus is significantly more divergent than all other human herpesviruses and highlight hot spots of diversity in the genome. Importantly, 75% of strains are not genetically intact but contain disruptive mutations in a diverse set of 26 genes, including the immunomodulatory genes UL40 and UL111A. These mutants are independent of culture passage artifacts and circulate in natural populations. Pervasive recombination, which is linked to the widespread occurrence of multiple infections, was found throughout the genome. The recombination density was significantly higher than those of other human herpesviruses and correlated with strain diversity. While the overall effects of strong purifying selection on virus evolution are apparent, evidence of diversifying selection was found in several genes encoding proteins that interact with the host immune system, including UL18, UL40, UL142, and UL147. These residues may present phylogenetic signatures of past and ongoing virus-host interactions. IMPORTANCEHuman cytomegalovirus has the largest genome of all viruses that infect humans. Currently, there is a great interest in establishing associations between genetic variants and strain pathogenicity of this herpesvirus. Since the number of publicly available full-genome sequences is limited, knowledge about strain diversity is highly fragmented and biased toward a small set of loci. Combined with our previous work, we have now contributed 101 complete genome sequences. We have used these data to conduct the first high-resolution analysis of interhost genome diversity, providing an unbiased and comprehensive overview of cytomegalovirus variability. These data are of major value to the development of novel antivirals and a vaccine and to identify potential targets for genotype-phenotype experiments. Furthermore, these data have enabled a thorough study of the evolutionary processes that have shaped cytomegalovirus diversity. Human cytomegalovirus (HCMV), the prototype member of the herpesvirus subfamily Betaherpesvirinae, is a widespread and important pathogen. Seroprevalence in the adult population ranges from 45% to 100% (1). After primary infection, HCMV establishes a lifelong, latent infection in myeloid progenitor cells (2). This virus causes mild to ...

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Cytomegalovirus alpha-chemokine genotypes are associated with clinical manifestations in children with congenital or postnatal infections

Cited by 12 publications

References 45 publications

Strain Variation and Disease Severity in Congenital Cytomegalovirus Infection

Strain Variation and Disease Severity in Congenital Cytomegalovirus Infection

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

High-Throughput Analysis of Human Cytomegalovirus Genome Diversity Highlights the Widespread Occurrence of Gene-Disrupting Mutations and Pervasive Recombination

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