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dc.contributor.authorGalitska, Ganna
dc.contributor.authorCoscia, Alessandra
dc.contributor.authorForni, Diego
dc.contributor.authorSteinbrueck, Lars
dc.contributor.authorDe Meo, Simone
dc.contributor.authorBiolatti, Matteo
dc.contributor.authorDe Andrea, Marco
dc.contributor.authorCagliani, Rachele
dc.contributor.authorLeone, Agata
dc.contributor.authorBertino, Enrico
dc.contributor.authorSchulz, Thomas
dc.contributor.authorSantoni, Angela
dc.contributor.authorLandolfo, Santo
dc.contributor.authorSironi, Manuela
dc.contributor.authorCerboni, Cristina
dc.contributor.authorDell'Oste, Valentina
dc.date.accessioned2021-05-03T17:15:10Z
dc.date.available2021-05-03T17:15:10Z
dc.date.issued2021-04-09
dc.identifier.urihttp://hdl.handle.net/10713/15557
dc.description.abstractHuman 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. © Copyright © 2021 Galitska, Coscia, Forni, Steinbrueck, De Meo, Biolatti, De Andrea, Cagliani, Leone, Bertino, Schulz, Santoni, Landolfo, Sironi, Cerboni and Dell’Oste.en_US
dc.description.urihttps://doi.org/10.3389/fimmu.2021.532484en_US
dc.language.isoenen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.ispartofFrontiers in Immunologyen_US
dc.rightsCopyright © 2021 Galitska, Coscia, Forni, Steinbrueck, De Meo, Biolatti, De Andrea, Cagliani, Leone, Bertino, Schulz, Santoni, Landolfo, Sironi, Cerboni and Dell’Oste.en_US
dc.subjectNK cellsen_US
dc.subjectcongenital infectionen_US
dc.subjectgenetic variabilityen_US
dc.subjecthuman cytomegalovirus (HCMV)en_US
dc.subjectimmunomodulationen_US
dc.subjectinnate immunityen_US
dc.subjectmultiple-strain infectionen_US
dc.subjectnext generation sequencingen_US
dc.titleGenetic Variability of Human Cytomegalovirus Clinical Isolates Correlates With Altered Expression of Natural Killer Cell-Activating Ligands and IFN-γen_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fimmu.2021.532484
dc.identifier.pmid33897679
dc.source.volume12
dc.source.beginpage532484
dc.source.endpage
dc.source.countrySwitzerland


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