Diagnosis-independent loss of T-cell costimulatory molecules in individuals with cytomegalovirus infection
Section snippets
Background
Lymphoproliferative response to mitogen, natural killer cell cytotoxicity, and virus-specific T-cell response are suppressed in a subset of depressed patients (Irwin and Miller, 2007, Zorrilla et al., 2001). Relevant to these findings is the link between depression and poor control of chronic viral infections (Evans et al., 2002, Phillips et al., 2008) and attenuated response to immunization or accelerated loss of vaccine-induced immunogenicity over time (Afsar et al., 2009, Ford et al., 2019b,
Study participants
The study was approved by the Western Institutional Review Board and was conducted according to the principles expressed in the Declaration of Helsinki. Volunteers gave written consent to participate in a study involving neuroimaging and immunophenotyping. One hundred participants with a diagnosis of MDD and 100 comparison controls with no personal history of a psychiatric disorder were included in this sub-study. The groups were matched for age and sex. Diagnoses were determined according to
Results
Of the 200 samples initially selected for analysis, three samples were excluded because of non-specific binding of the CD45RA-PE-Cy7 antibody and one was excluded due to lack of remaining plasma for CMV antibody testing. Within the MDD group there was no difference between CMV+ and CMV− subjects in MADRS scores or in recent history of psychotropic medication use other than sleep aids (p’s > 0.10). ETI-SR and CTQ scores were higher in MDD compared to controls (p’s < 0.001) and in CMV+ compared
Discussion
This investigation tested the hypothesis that there is an interaction between CMV and depression such that young and middle-aged adults with MDD who are also CMV+ would have greater premature accumulation of age-related T-cell phenotypes than non-depressed CMV+ controls. There were two main results. The principal finding was that no such interaction was evident. Although CMV infection was associated with an age-related T-cell phenotype, this relationship was independent of MDD diagnosis.
Acknowledgments
The authors thank all the research participants and wish to acknowledge the contributions of Brenda Davis, Debbie Neal, Chibing Tan, and Ashlee Rempel from the laboratory of TKT at the University of Oklahoma Integrative Immunology Center towards the transport, processing, and handling of all blood samples.
Funding
This work has been supported in part by The William K. Warren Foundation, National Institute of Mental Health Award Number R21MH113871, and the National Institute of General Medical Sciences Center Grant Award Number 1P20GM121312. RY has received support from the Stanley Medical Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Financial disclosures
Dr. Paulus has received royalties for an article about methamphetamine use disorder from UpToDate. The other authors have no disclosures.
Ethics Statement
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
References (64)
- et al.
Antibody response following hepatitis B vaccination in dialysis patients: does depression and life quality matter?
Vaccine
(2009) - et al.
Development and validation of a brief screening version of the Childhood Trauma Questionnaire
Child Abuse Negl.
(2003) - et al.
CMV-specific T-cells and CD27-CD28-CD4+ T-cells for assignment of cytomegalovirus (CMV) status in adults awaiting organ transplant
J. Clin. Virol.
(2019) - et al.
Human cytomegalovirus quantification in toddlers saliva from day care centers and emergency unit: a feasibility study
J. Clin. Virol.
(2014) - et al.
Major depressive disorder and immunity to varicella-zoster virus in the elderly
Brain Behav. Immun.
(2011) - et al.
Depressive disorders and immunity: 20 years of progress and discovery
Brain Behav. Immun.
(2007) - et al.
Childhood environments and cytomegalovirus serostatus and reactivation in adults
Brain Behav. Immun.
(2014) - et al.
Antiphospholipid, antinuclear, Epstein-Barr and cytomegalovirus antibodies, and soluble interleukin-2 receptors in depressive patients
J. Affect. Disord.
(1991) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other
Am. J. Hum. Genet.
(2004)- et al.
Cytomegalovirus is associated with depression and anxiety in older adults
Brain Behav. Immun.
(2008)
Associations between chronic caregiving stress and T cell markers implicated in immunosenescence
Brain Behav. Immun.
A novel link between stress and human cytomegalovirus (HCMV) infection: sympathetic hyperactivity stimulates HCMV activation
Virology
Consistent associations between measures of psychological stress and CMV antibody levels in a large occupational sample
Brain Behav. Immun.
A longitudinal study of the stability, variability, and interdependencies among late-differentiated T and NK cell subsets in older adults
Exp. Gerontol.
Herpesviruses, inflammatory markers and incident depression in a longitudinal study of Detroit residents
Psychoneuroendocrinology
Differences in the association between persistent pathogens and mood disorders among young- to middle-aged women and men in the U.S
Brain Behav. Immun.
Psychoneuroendocrinological links between chronic stress and depression
Prog. Neuropsychopharmacol. Biol. Psychiatr.
Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients
Brain Behav. Immun.
Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly
Hum. Immunol.
The chronic mild stress (CMS) model of depression: history, evaluation and usage
Neurobiol. Stress
The relationship of depression and stressors to immunological assays: a meta-analytic review
Brain Behav. Immun.
Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons
J. Virol.
Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule
Vitro Cell. Dev. Biol. Anim.
Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections
Nat. Med.
Psychometric properties of the early trauma inventory-self report
J. Nerv. Ment. Dis.
Functional properties of T lymphocytes and their subsets in cytomegalovirus mononucleosis
J. Immunol.
A simple correction for multiple comparisons in interval mapping genome scans
Heredity
Statistical Power Analysis for the Behavioral Sciences
Contemporaneous fluctuations in T cell responses to persistent herpes virus infections
Eur. J. Immunol.
Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans
J. Gen. Virol.
Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III
Epidemiol. Infect.
Family poverty is associated with cytomegalovirus antibody titers in U.S. children
Health Psychol.
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