title: Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses.
abstract: Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMV-seronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C+NK cells, CD16+Vδ2(-) γδ T cells, and conventional HCMV-specific CD8+T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCEHCMV-specific immune responses have been extensively documented in immunocompromised patients and duringin uteroacquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.
authors.affiliation: Etablissement Français du Sang, Nantes, France.|CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Riou
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, Université de Nantes, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.|Service de Virologie,CHU Nantes, Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bressollette-Bodin
authors.affiliation: Service des Maladies Infectieuses et Tropicales, CHU Nantes, Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Boutoille
authors.affiliation: Etablissement Français du Sang, Nantes, France.|CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.|Laboratoire d'Histocompatibilité et d'Immunogénétique, EFS Nantes, Nantes, France.|LabEx Transplantex, Université de Strasbourg, Strasbourg, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Gagne
authors.affiliation: Service de Virologie,CHU Nantes, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Rodallec
authors.affiliation: Service des Maladies Infectieuses et Tropicales, CHU Nantes, Nantes, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Lefebvre
authors.affiliation: Service des Maladies Infectieuses et Tropicales, CHU Nantes, Nantes, France.
authors.forename: François
authors.initials: F
authors.lastname: Raffi
authors.affiliation: Division of Hematology and Bone Marrow Transplantation, City of Hope, National Medical Center, Duarte, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Senitzer
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, Université de Nantes, Nantes, France.|Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.|Service de Virologie,CHU Nantes, Nantes, France.
authors.forename: Berthe-Marie
authors.initials: BM
authors.lastname: Imbert-Marcille
authors.affiliation: Etablissement Français du Sang, Nantes, France christelle.retiere@efs.sante.fr.|CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Retière
mesh_terms: D056704:Adaptive Immunity; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000502:physiology; D018655:Lymphocyte Count; D008218:Lymphocytosis / Q000821:virology; D008297:Male; D008875:Middle Aged; D059467:Transcriptome; D055815:Young Adult
keywords: HCMV; NK cells; T lymphocytes; adaptive immunity; innate immunity