Genotypic Diversity and Mixed Infection in Newborn Disease and Hearing Loss in Congenital Cytomegalovirus Infection

Pati, Sunil; Pinninti, Swetha; Novák, Zdeněk; Chowdhury, Nazma; Patro, A. Raj Kumar; Fowler, Karen B.; Ross, Shannon A.; Boppana, Suresh B.

doi:10.1097/inf.0b013e31829bb0b9

Cited by 41 publications

(53 citation statements)

References 34 publications

(49 reference statements)

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“…6,7 However, the claims are controversial. 8 In Cuba, a preceding study performed in Havana showed an intermediate rate (1.1%) of CMV congenital infection in newborns (NB) and a 92.7% of seroprevalence in pregnant women (PW). 9 However, the frequency of symptomatic CMV congenital infection across the country, and its association with gB genotype, viral load and clinical symptoms has never been studied.…”

Section: Introductionmentioning

confidence: 98%

Diagnosis, gB genotype distribution and viral load of symptomatic congenitally infected CMV patients in Cuba

et al. 2016

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This study showed that CMV is a frequent cause of congenital infection in symptomatic Cuban patients. Despite gB2 being the most frequently detected, gB-4 was the only genotype associated with clinical features (sepsis-like syndrome in NB). No other associations among specific genotypes and clinical characteristics were found. Further studies are needed to clarify the role that viral load and genotype play in the outcome of congenital infection.

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Section: Introductionmentioning

confidence: 98%

Diagnosis, gB genotype distribution and viral load of symptomatic congenitally infected CMV patients in Cuba

et al. 2016

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“…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). Overall, these studies have focused on one or, at best, a few genes at a time, ignoring the influence of other variable regions in the genome.…”

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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

156

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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“…The fetal brain and auditory system are the main sites of the clinical manifestations of congenital HCMV (cCMV) infection (1)(2)(3)(4), and sensorineural hearing loss is the most common long-term sequela in congenitally infected infants (4)(5)(6). In the fetal brain, the bilateral subventricular zone (SVZ), where neural progenitor/stem cells (NPCs) are a predominant cell type, is a site of virus-induced damage that has been well described in infants with severe congenital HCMV infection (7)(8)(9)(10)(11).…”

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confidence: 99%

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Liu

Yang

et al. 2015

J Virol

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Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.

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Genotypic Diversity and Mixed Infection in Newborn Disease and Hearing Loss in Congenital Cytomegalovirus Infection

Cited by 41 publications

References 34 publications

Diagnosis, gB genotype distribution and viral load of symptomatic congenitally infected CMV patients in Cuba

Diagnosis, gB genotype distribution and viral load of symptomatic congenitally infected CMV patients in Cuba

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

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

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