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      Low Interferon Relative-Response to Cytomegalovirus Is Associated with Low Likelihood of Intrauterine Transmission of the Virus

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          Abstract

          Background

          Congenital Cytomegalovirus (CMV) is a very common intrauterine infection which can cause severe mental and hearing impairments. Notably, only 40% of primarily infected women transmit CMV to the fetus. CMV-specific T-cell response has a role in CMV disease but individual immune heterogeneity precludes reliable correlation between measurable T-cells response and intrauterine transmission.

          Study Aim

          To establish a correlation between maternal T-cells response and fetal CMV transmission using an individual normalized immune response.

          Methods

          We analyzed IFN-γ secretion upon whole blood stimulation from primary CMV-infected pregnant women, with either CMV-peptides or PHA-mitogen.

          Results

          We established a new normalization method of individual IFN-γ response to CMV by defining the ratio between specific-CMV response and non-specific mitogen response (defined as IFN-γ relative response, RR), aiming to overcome high person-to-person immune variability. We found a unique subpopulation of women with low IFN-γ RR strongly correlated with absence of transmission. IFN-γ RR lower than 1.8% (threshold determined by ROC analysis) reduces the pre-test probability of transmission from 40% to 8%, revealing an unexpected link between low IFN-γ RR and non-transmission.

          Conclusion

          In pregnant women with primary CMV infection, low IFN-γ RR is associated with low risk of transmission.

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          Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant.

          Maria Revello, Giuseppe Gerna (2002)
          Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection and mental retardation. HCMV infection, while causing asymptomatic infections in most immunocompetent subjects, can be transmitted during pregnancy from the mother with primary (and also recurrent) infection to the fetus. Hence, careful diagnosis of primary infection is required in the pregnant woman based on the most sensitive serologic assays (immunoglobulin M [IgM] and IgG avidity assays) and conventional virologic and molecular procedures for virus detection in blood. Maternal prognostic markers of fetal infection are still under investigation. If primary infection is diagnosed in a timely manner, prenatal diagnosis can be offered, including the search for virus and virus components in fetal blood and amniotic fluid, with fetal prognostic markers of HCMV disease still to be defined. However, the final step for definite diagnosis of congenital HCMV infection is detection of virus in the blood or urine in the first 1 to 2 weeks of life. To date, treatment of congenital infection with antiviral drugs is only palliative both prior to and after birth, whereas the only efficacious preventive measure seems to be the development of a safe and immunogenic vaccine, including recombinant, subunit, DNA, and peptide-based vaccines now under investigation. The following controversial issues are discussed in the light of the most recent advances in the field: the actual perception of the problem; universal serologic screening before pregnancy; the impact of correct counseling on decision making by the couple involved; the role of prenatal diagnosis in ascertaining transmission of virus to the fetus; the impact of preconceptional and periconceptional infections on the prevalence of congenital infection; and the prevalence of congenitally infected babies born to mothers who were immune prior to pregnancy compared to the number born to mothers undergoing primary infection during pregnancy.
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            Congenital cytomegalovirus (CMV) epidemiology and awareness.

            Michael J. Cannon (2009)
            This commentary highlights and discusses the implications of a number of recent studies that refine epidemiologic knowledge of CMV infection and assess awareness of congenital CMV among clinicians and the public. These studies highlight that: (1) congenital CMV results in a disease burden that is substantial and severe; (2) a high proportion of United States women of reproductive age are susceptible to CMV infection; (3) the majority of congenital CMV infections in the United States result from recurrent infections among pregnant women; (4) CMV seroprevalence and seroincidence are much higher among racial/ethnic minorities and persons of lower socioeconomic status (SES); (5) household transmission of CMV appears to be an important transmission route in the United States; (6) sexual transmission of CMV appears to be an important transmission route in some population sub-groups in the United States; (7) women have limited awareness and knowledge about congenital CMV; (8) most obstetrician/gynecologists do not counsel women about prevention of congenital CMV; (9) most women view CMV prevention messages positively.
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              Development of human cytomegalovirus-specific T cell immunity during primary infection of pregnant women and its correlation with virus transmission to the fetus.

              Maria Revello, Milena Furione, Maurizio Zavattoni … (2007)
              We sought to study the development of human cytomegalovirus (HCMV)-specific T cell-mediated immune responses during primary HCMV infection in pregnancy. The HCMV-specific lymphoproliferative response (LPR) and intracellular cytokine (interferon [IFN]- gamma and interleukin [IL]-2) production were investigated during the first year after primary infection in 49 pregnant women and 9 nonpregnant control subjects. An HCMV-specific CD4(+) and CD8(+) T cell LPR was detected by the 5,6-carboxyfluorescein diacetate succinimidyl ester dilution method, and a cell-division index was calculated. The CD4(+) T cell LPR developed slightly earlier than the CD8(+) T cell LPR. However, CDI values for both T cell subpopulations were lower than those of seropositive control subjects in both pregnant and nonpregnant individuals. During the first month after infection, IFN- gamma -producing CD4(+) and CD8(+) T cells were consistently observed, whereas IL-2-producing T cells were very rarely detected in blood. A correlation between the development of HCMV-specific LPR and virus clearance from blood was observed. A significantly delayed development of the CD4(+) T cell LPR was observed in infected mothers who transmitted virus to the fetus, compared with those who did not. The development of adaptive T cell immunity after primary HCMV infection appears to be a complex and slow process until a memory T cell response develops. The T cell immune response appears to influence vertical HCMV transmission.
              Article 0 comments Cited 36 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ana Claudia Zenclussen: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 16 February 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 2
                Electronic Location Identifier: e0147883
                Affiliations
                [1 ]Research Laboratory of Infectious Diseases, Shaare Zedek Medical Center, affiliated to the Hebrew University Medical School, Jerusalem, Israel
                [2 ]Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel
                [3 ]Microbiology @ Immunology laboratories, Shaare Zedek Medical Center, Jerusalem, Israel
                Medical Faculty, Otto-von-Guericke University Magdeburg, Medical Faculty, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YS YEY. Performed the experiments: MH GA EB RF YEY. Analyzed the data: MBM YEY YS. Contributed reagents/materials/analysis tools: MA. Wrote the paper: YS YEY MBM.

                Article
                Publisher ID: PONE-D-15-47826
                DOI: 10.1371/journal.pone.0147883
                PMC ID: 4755570
                PubMed ID: 26881863
                SO-VID: 72e1547f-70ca-4451-ac69-c22b93e77f1d
                Copyright © © 2016 Eldar-Yedidia et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 1 November 2015
                Date accepted : 8 January 2016
                Page count
                Figures: 5, Tables: 1, Pages: 12
                Funding
                This study was funded by internal research grants of the Hospital.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Response
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Response
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Cycle and Cell Division
                Subject: Mitogens
                Subject: Medicine and Health Sciences
                Subject: Infectious Diseases
                Subject: Viral Diseases
                Subject: Cytomegalovirus Infection
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Blood
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: DNA viruses
                Subject: Herpesviruses
                Subject: Human Cytomegalovirus
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Herpesviruses
                Subject: Human Cytomegalovirus
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Herpesviruses
                Subject: Human Cytomegalovirus
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Herpesviruses
                Subject: Human Cytomegalovirus
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Bacteria
                Subject: Actinobacteria
                Subject: Mycobacterium Tuberculosis
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Secretion
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Secretion
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                Data Availability All relevant data are within the paper and its Supporting Information file.

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