Top

BMC Infectious Diseases

Published in:

Open Access 01-12-2021 | Research article

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

Authors: Christian Berg, Mette M. Rosenkilde, Thomas Benfield, Lene Nielsen, Thomas Sundelin, Hans R. Lüttichau

Published in: BMC Infectious Diseases | Issue 1/2021

Abstract

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.

Available only for authorised users

Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20(4):202–13. https://doi.org/10.1002/rmv.655.CrossRefPubMed

Noyola DE, Valdez-Lopez BH, Hernandez-Salinas AE, Santos-Diaz MA, Noyola-Frias MA, Reyes-Macias JF, et al. Cytomegalovirus excretion in children attending day-care centers. Arch Med Res. 2005;36(5):590–3. https://doi.org/10.1016/j.arcmed.2005.03.045.CrossRefPubMed

Grosjean J, Trapes L, Hantz S, Mengelle C, Virey B, Undreiner F, et al. Human cytomegalovirus quantification in toddlers saliva from day care centers and emergency unit: a feasibility study. J Clin Virol. 2014;61(3):371–7. https://doi.org/10.1016/j.jcv.2014.07.020.CrossRefPubMed

Amin MM, Bialek SR, Dollard SC, Wang C. Urinary Cytomegalovirus shedding in the United States: the National Health and nutrition examination surveys, 1999-2004. Clin Infect Dis. 2018;67(4):587–92. https://doi.org/10.1093/cid/ciy143.CrossRefPubMed

Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–63. https://doi.org/10.1002/rmv.544.CrossRefPubMed

Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–76. https://doi.org/10.1002/rmv.535.CrossRefPubMed

Institute of Medicine Committee to Study Priorities for Vaccine D. The National Academies Collection: Reports funded by National Institutes of Health. In: Stratton KR, Durch JS, Lawrence RS, editors. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington (DC): National Academies Press (US). Copyright 2000 by the National Academy of Sciences. All rights reserved; 2000.

Sijmons S, Thys K, Mbong Ngwese M, Van Damme E, Dvorak J, Van Loock M, et al. High-throughput analysis of human cytomegalovirus genome diversity highlights the widespread occurrence of gene-disrupting mutations and pervasive recombination. J Virol. 2015;89(15):7673–95. https://doi.org/10.1128/JVI.00578-15.CrossRefPubMedPubMedCentral

Suarez NM, Wilkie GS, Hage E, Camiolo S, Holton M, Hughes J, et al. Human cytomegalovirus genomes sequenced directly from clinical material: variation, multiple-strain infection, recombination, and gene loss. J Infect Dis. 2019;220(5):781–91. https://doi.org/10.1093/infdis/jiz208.CrossRefPubMedPubMedCentral

10.

Luttichau HR. The cytomegalovirus UL146 gene product vCXCL1 targets both CXCR1 and CXCR2 as an agonist. J Biol Chem. 2010;285(12):9137–46. https://doi.org/10.1074/jbc.M109.002774.CrossRefPubMed

11.

Penfold ME, Dairaghi DJ, Duke GM, Saederup N, Mocarski ES, Kemble GW, et al. Cytomegalovirus encodes a potent alpha chemokine. Proc Natl Acad Sci U S A. 1999;96(17):9839–44. https://doi.org/10.1073/pnas.96.17.9839.CrossRefPubMedPubMedCentral

12.

Cha TA, Tom E, Kemble GW, Duke GM, Mocarski ES, Spaete RR. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol. 1996;70(1):78–83. https://doi.org/10.1128/JVI.70.1.78-83.1996.CrossRefPubMedPubMedCentral

13.

Jackson JW, Hancock TJ, LaPrade E, Dogra P, Gann ER, Masi TJ, et al. The human cytomegalovirus chemokine vcxcl-1 modulates normal dissemination kinetics of murine cytomegalovirus In Vivo. mBio. 2019;10(3):e01289-19. https://doi.org/10.1128/mBio.01289-19.

14.

Dolan A, Cunningham C, Hector RD, Hassan-Walker AF, Lee L, Addison C, et al. Genetic content of wild-type human cytomegalovirus. J Gen Virol. 2004;85(Pt 5):1301–12. https://doi.org/10.1099/vir.0.79888-0.CrossRefPubMed

15.

Heo J, Dogra P, Masi TJ, Pitt EA, de Kruijf P, Smit MJ, et al. Novel human cytomegalovirus viral chemokines, vCXCL-1s, display functional selectivity for neutrophil signaling and function. J Immunol. 2015;195(1):227–36. https://doi.org/10.4049/jimmunol.1400291.CrossRefPubMed

16.

Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, et al. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev. 2014;66(1):1–79. https://doi.org/10.1124/pr.113.007724.CrossRefPubMedPubMedCentral

17.

Clark-Lewis I, Dewald B, Geiser T, Moser B, Baggiolini M. Platelet factor 4 binds to interleukin 8 receptors and activates neutrophils when its N terminus is modified with Glu-Leu-Arg. Proc Natl Acad Sci U S A. 1993;90(8):3574–7. https://doi.org/10.1073/pnas.90.8.3574.CrossRefPubMedPubMedCentral

18.

Hebert CA, Vitangcol RV, Baker JB. Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding. J Biol Chem. 1991;266(28):18989–94. https://doi.org/10.1016/S0021-9258(18)55160-7.CrossRefPubMed

19.

Kufareva I, Gustavsson M, Zheng Y, Stephens BS, Handel TM. What do structures tell us about chemokine receptor function and antagonism? Annu Rev Biophys. 2017;46(1):175–98. https://doi.org/10.1146/annurev-biophys-051013-022942.CrossRefPubMedPubMedCentral

20.

Paradowska E, Jablonska A, Plociennikowska A, Studzinska M, Suski P, Wisniewska-Ligier M, et al. Cytomegalovirus alpha-chemokine genotypes are associated with clinical manifestations in children with congenital or postnatal infections. Virology. 2014;462–463:207–17.CrossRefPubMed

21.

Guo G, Zhang L, Ye S, Hu Y, Li B, Sun X, et al. Polymorphisms and features of cytomegalovirus UL144 and UL146 in congenitally infected neonates with hepatic involvement. PLoS One. 2017;12(2):e0171959. https://doi.org/10.1371/journal.pone.0171959.CrossRefPubMedPubMedCentral

22.

Arav-Boger R, Foster CB, Zong JC, Pass RF. Human cytomegalovirus-encoded alpha -chemokines exhibit high sequence variability in congenitally infected newborns. J Infect Dis. 2006;193(6):788–91. https://doi.org/10.1086/500508.CrossRefPubMed

23.

He R, Ruan Q, Qi Y, Ma YP, Huang YJ, Sun ZR, et al. Sequence variability of human cytomegalovirus UL146 and UL147 genes in low-passage clinical isolates. Intervirology. 2006;49(4):215–23. https://doi.org/10.1159/000091468.CrossRefPubMed

24.

Heo J, Petheram S, Demmler G, Murph JR, Adler SP, Bale J, et al. Polymorphisms within human cytomegalovirus chemokine (UL146/UL147) and cytokine receptor genes (UL144) are not predictive of sequelae in congenitally infected children. Virology. 2008;378(1):86–96. https://doi.org/10.1016/j.virol.2008.05.002.CrossRefPubMed

25.

Barbi M, Binda S, Caroppo S. Diagnosis of congenital CMV infection via dried blood spots. Rev Med Virol. 2006;16(6):385–92. https://doi.org/10.1002/rmv.517.CrossRefPubMed

26.

Atkinson C, Walter S, Sharland M, Tookey P, Luck S, Peckham C, et al. Use of stored dried blood spots for retrospective diagnosis of congenital CMV. JMedVirol. 2009;81(8):1394–8.

27.

Boppana SB, Ross SA, Novak Z, Shimamura M, Tolan RW Jr, Palmer AL, et al. Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA. 2010;303(14):1375–82. https://doi.org/10.1001/jama.2010.423.CrossRefPubMedPubMedCentral

28.

Pellegrinelli L, Galli C, Primache V, Alde M, Fagnani E, Di Berardino F, et al. Diagnosis of congenital CMV infection via DBS samples testing and neonatal hearing screening: an observational study in Italy. BMC Infect Dis. 2019;19(1):652. https://doi.org/10.1186/s12879-019-4296-5.CrossRefPubMedPubMedCentral

29.

Berg C, Friis MB, Rosenkilde MM, Benfield T, Nielsen L, Luttichau HR, et al. Development of highly efficient protocols for extraction and amplification of cytomegalovirus DNA from dried blood spots for detection and genotyping of polymorphic immunomodulatory genes. PLoS One. 2019;14(9):e0222053. https://doi.org/10.1371/journal.pone.0222053.CrossRefPubMedPubMedCentral

30.

Pedersen CB, Gotzsche H, Moller JO, Mortensen PB. The Danish civil registration system. A cohort of eight million persons. Dan Med Bull. 2006;53(4):441–9.PubMed

31.

Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39(7 Suppl):30–3. https://doi.org/10.1177/1403494811401482.CrossRefPubMed

32.

Renzette N, Gibson L, Bhattacharjee B, Fisher D, Schleiss MR, Jensen JD, et al. Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection. PLoS Genet. 2013;9(9):e1003735. https://doi.org/10.1371/journal.pgen.1003735.CrossRefPubMedPubMedCentral

33.

Yamaguchi J, Olivo A, Laeyendecker O, Forberg K, Ndembi N, Mbanya D, et al. Universal target capture of HIV sequences from NGS libraries. Front Microbiol. 2018;9:2150. https://doi.org/10.3389/fmicb.2018.02150.CrossRefPubMedPubMedCentral

34.

Halwachs-Baumann G, Genser B, Pailer S, Engele H, Rosegger H, Schalk A, et al. Human cytomegalovirus load in various body fluids of congenitally infected newborns. J Clin Virol. 2002;25(Suppl 3):S81–7.CrossRefPubMed

35.

Barbi M, Binda S, Primache V, Caroppo S, Dido P, Guidotti P, et al. Cytomegalovirus DNA detection in Guthrie cards: a powerful tool for diagnosing congenital infection. JClinVirol. 2000;17(3):159–65.

36.

Soetens O, Vauloup-Fellous C, Foulon I, Dubreuil P, De SB, Grangeot-Keros L, et al. Evaluation of different cytomegalovirus (CMV) DNA PCR protocols for analysis of dried blood spots from consecutive cases of neonates with congenital CMV infections. JClinMicrobiol. 2008;46(3):943–6.

37.

Vives-Onos I, Codina-Grau MG, Noguera-Julian A, Blazquez-Gamero D, Fortuny C, Baquero-Artigao F, et al. Is polymerase chain reaction in neonatal dried blood spots reliable for the diagnosis of congenital Cytomegalovirus infection? Pediatr Infect Dis J. 2019;38(5):520–4. https://doi.org/10.1097/INF.0000000000002144.CrossRefPubMed

38.

Kimberlin DW, Acosta EP, Sanchez PJ, Sood S, Agrawal V, Homans J, et al. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis. 2008;197(6):836–45. https://doi.org/10.1086/528376.CrossRefPubMed

Title: The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population
Authors: Christian Berg
Mette M. Rosenkilde
Thomas Benfield
Lene Nielsen
Thomas Sundelin
Hans R. Lüttichau
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: BMC Infectious Diseases / Issue 1/2021
Electronic ISSN: 1471-2334
DOI: https://doi.org/10.1186/s12879-021-06076-w

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Increase in consumption of alcohol-based hand rub in German acute care hospitals over a 12 year period

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

Lack of association between vitamin D insufficiency and clinical outcomes of patients with COVID-19 infection

Dynamic changes in lymphocyte subsets and parallel cytokine levels in patients with severe and critical COVID-19

Coronavirus seasonality, respiratory infections and weather

Self-rated health among people living with HIV in Spain in 2019: a cross-sectional study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page