Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples

Abstract

Cytomegalovirus (CMV) is a common, neurotrophic herpesvirus that can be reactivated by inflammation and cause central nervous system disease. We hypothesize that CMV may contribute to the neuroinflammation that underlies some psychiatric disorders by (1) exacerbating inflammation through the induction of anti-viral immune responses, and (2) translating peripheral inflammation into neuroinflammation. We investigated whether the presence of anti-CMV antibodies in blood were associated with mental illness, suicide, neuroinflammation, and microglial density in the dorsolateral prefrontal cortex (DLPFC) in postmortem samples. Data (n = 114 with schizophrenia; n = 78 with bipolar disorder; n = 87 with depression; n = 85 controls) were obtained from the Stanley Medical Research Institute. DLPFC gene expression data from a subset of 82 samples were categorized into "high" (n = 30), and "low" (n = 52) inflammation groups based on a recursive two-step cluster analysis using expression data for four inflammation-related genes. Measurements of the ratio of non-ramified to ramified microglia, a proxy of microglial activation, were available for a subset of 49 samples. All analyses controlled for age, sex, and ethnicity, as well as postmortem interval, and pH for gene expression and microglial outcomes. CMV seropositivity significantly increased the odds of a mood disorder diagnosis (bipolar disorder: OR = 2.45; major depression: OR = 3.70) and among the psychiatric samples, of suicide (OR = 2.09). Samples in the upper tercile of anti-CMV antibody titers were more likely to be members of the "high" inflammation group (OR = 4.41, an effect driven by schizophrenia and bipolar disorder samples). CMV positive samples also showed an increased ratio of non-ramified to ramified microglia in layer I of the DLPFC (Cohen's d = 0.81) as well as a non-significant increase in this ratio for the DLPFC as a whole (d = 0.56). The results raise the possibility that the reactivation of CMV contributes to the neuroinflammation that underlies some cases of psychiatric disorders.

Figure 1.

Sample inclusion and exclusion flowchart.

Figure 2.

Associations between CMV infection and psychiatric disorders. A, Relative to CMV seronegative samples, CMV seropositive samples are associated with increased odds of having a psychiatric disorder (defined as a binary outcome: having a psychiatric disorder diagnosis was coded as 1, and control samples were coded as 0). B, CMV seropositive samples were grouped into 3 groups (low, medium, and high) based on the percentile of antibody IgG levels. Relative to CMV negative samples, medium and high CMV antibody IgG levels are associated with significantly increased odds of having a psychiatric disorder.

Figure 3.

Associations between CMV infection and suicide status. A, Relative to CMV seronegative samples, CMV seropositive samples are associated with an increased likelihood of dying by suicide. B, CMV seropositive samples were grouped into 3 groups (low, medium, and high) based on the percentile of antibody IgG levels. Relative to CMV negative samples, both low and high CMV antibody IgG levels are associated with an increased likelihood of dying by suicide.

Figure 4.

Associations between CMV infection and microglia activation. A, Ramified microglia displayed small, round cell bodies with numerous thin, branched processes, whereas B, non-ramified microglia displayed enlarged or amorphous soma, and processes that were thickened, fewer in number or absent. C, CMV seropositivity is associated with an increased ratio of non-ramified to ramified microglia. Note that the figure illustrates the ratio after regressing out the effects of age, PMI, sex, brain pH, and diagnosis.