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 neurological disease. CMV replication can in turn worsen inflammation, raising the possibility that poorly controlled CMV infections may contribute to the neuroinflammation underlying some psychiatric disorders. 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 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. Gene expression data from a subset of 82 cases 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 density of non-ramified and ramified microglia were available for an independent subset of 51 samples. All analyses controlled for age, sex, ethnicity, postmortem interval, and pH. CMV seropositivity significantly increased the odds of a mood disorder diagnosis (bipolar disorder: OR = 2.49; major depression: OR = 2.62) and among the psychiatric cases, of suicide (OR = 2.21). Samples in the upper tercile of anti-CMV antibody titers were more likely to be members of the “high” inflammation group (OR = 4.41). CMV positive cases also showed an increased ratio of non-ramified to ramified microglia in layer I of the dorsolateral prefrontal cortex (Cohen’s d = 0.81). The results raise the possibility that the reactivation of CMV contributes to the neuroinflammation that underlies some cases of psychiatric disorders.

Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder

“…The gut microbiome has been implicated in MDD 70,71 and it is conceivable that NLRC4 in ammasomes activated by gut bacterial agellin may play an unrecognized role in this relationship. In addition, the increase in NLRC4 expression raises the possibility of a viral etiology as we have previously hypothesized [72][73][74][75] , but it is also possible that the effect is driven by ER stress. The NLRP3 in ammasome, which is activated by a wide variety of endogenous danger signals and cellular stressors [12][13][14] , has previously been implicated in MDD [25][26][27][28] .…”