Abstract
Early-life infections and associated neuroinflammation is incriminated in the pathogenesis of various mood disorders. Infection with human roseoloviruses, HHV-6A and HHV-6B, allows viral latency in the central nervous system and other tissues, which can later be activated causing cognitive and behavioral disturbances. Hence, this study was designed to evaluate possible association of HHV-6A and HHV-6B activation with three different groups of psychiatric patients. DNA qPCR, immunofluorescence and FISH studies were carried out in post-mortem posterior cerebellum from 50 cases each of bipolar disorder (BPD), schizophrenia, 15 major depressive disorder (MDD) and 50 appropriate control samples obtained from two well-known brain collections (Stanley Medical Research Institute). HHV-6A and HHV-6B late proteins (indicating active infection) and viral DNA were detected more frequently (p < 0.001 for each virus) in human cerebellum in MDD and BPD relative to controls. These roseolovirus proteins and DNA were found less frequently in schizophrenia cases. Active HHV-6A and HHV-6B infection in cerebellar Purkinje cells were detected frequently in BPD and MDD cases. Furthermore, we found a significant association of HHV-6A infection with reduced Purkinje cell size, suggesting virus-mediated abnormal Purkinje cell function in these disorders. Finally, gene expression analysis of cerebellar tissue revealed changes in pathways reflecting an inflammatory response possibly to HHV-6A infection. Our results provide molecular evidence to support a role for active HHV-6A and HHV-6B infection in BPD and MDD.
Highlights
Heritable as well as environmental factors, those that lead to neuroinflammation early in life, might play an important etiologic role in bipolar disorder (BPD), major depressive disorder (MDD), and schizophrenia (SCZ) (Schmitt et al, 2014)
The roseolovirus genus of betaherpesviruses consisting of human herpesvirus (HHV) HHV-6A, HHV-6B, and HHV-7 infect a large fraction of the human population, leading to viral latency in various organs/tissues including the central nervous system (CNS), salivary glands, accompanied by periodic reactivation (Agut et al, 2015)
To detect cell-specific infection by HHV-6A or HHV-6B, we examined the presence of HHV-6A and HHV-6B late proteins, gp82/105 and OHV3 respectively, as a marker of active viral infection, using immunofluorescence analysis (IFA) staining in both cohorts
Summary
Heritable as well as environmental factors, those that lead to neuroinflammation early in life, might play an important etiologic role in bipolar disorder (BPD), major depressive disorder (MDD), and schizophrenia (SCZ) (Schmitt et al, 2014). Prenatal maternal infection with influenza type A, Toxoplasma gondii, measles or rubella increases disease risk in SCZ (Hagberg et al, 2012). Prenatal exposure to influenza leads to a fourfold increase in the risk of developing BPD (Parboosing et al, 2013) and a meta-analysis of MDD reported association with Borna disease virus and members of the herpesvirus family HSV-1, HHV-3, and HHV-4 (Wang et al, 2014). Childhood hospitalizations for viral and non-viral infection are associated with an increased risk of developing SCZ, MDD, and BPD (Khandaker et al, 2012; Benros et al, 2013). The roseolovirus genus of betaherpesviruses consisting of human herpesvirus (HHV) HHV-6A, HHV-6B, and HHV-7 infect a large fraction of the human population, leading to viral latency in various organs/tissues including the central nervous system (CNS), salivary glands, accompanied by periodic reactivation (Agut et al, 2015). HHV-6A and HHV-6B are known to be neurotropic, signs of active infection, i.e., the presence of late proteins expressed immediately after the replicative cycle–have not previously been investigated in brain tissue in psychiatric illness (Luppi et al, 1994; Challoner et al, 1995; Chan et al, 2001; Cuomo et al, 2001; Esposito et al, 2015)
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