Alex Moir ’23

Human herpesvirus 6B (HHV-6B) is one of the most prevalent herpesviruses amongst tested populations, with estimates placing worldwide infections near 100%. HHV-6B is neurotropic, establishing a lifelong infection in the brain and entering a period of latency in which replication and spread is inhibited. The activity of HHV-6B and its effects on the brain during latent infection are poorly understood. Examination of postmortem brains of patients with mood disorders revealed altered HHV-6B activity, meriting further investigation into the possible role of HHV-6B on mental health. A study by Dr. Nobuyuki Kobayashi and his team of researchers at Jikei University School of Medicine identified SITH-1, a protein specific to HHV-6B latent infection. In infected mice, they found that increased expression of SITH-1 at HHV-6B latent infection sites mediated hypothalamic-pituitary-adrenal (HPA) axis induced stress responses and predisposition to depressive symptoms. 

Researchers first searched for protein transcripts associated with HHV-6B reactivation by analyzing gene homologs for latent reactivation associated protein transcripts in human cytomegalovirus (HCMV), a close relative to HHV-6B. High amino acid homology with a latent HCMV transcript revealed a novel transcript for SITH-1. To model SITH-1 activity independent of HHV-6B latent infection, researchers then engineered mice expressing SITH-1 in their olfactory astrocytes, or nerve-adjacent immune cells that are a primary site of HHV-6B infection. SITH-1 mice were subjected to cage tilt and tail suspension tests to induce a stress response. These mice exhibited decreased sucrose consumption compared to control mice, indicating a depressive response. Additionally, in cage tilt tested SITH-1 mice, mRNA sequencing showed upregulation for activation markers of the HPA axis, which generates neuroendocrine stress responses. Immunostaining combined with confocal microscopy revealed SITH-1 forms a complex with CAML, a channel protein that controls the influx of calcium ions into olfactory astrocytic cells. This SITH-1-CAML complex resulted in excess calcium influx and cell death in the olfactory bulb, which is associated with depressive symptoms. 

After establishing this mechanism of action, the researchers tested human blood samples for SITH-1-CAML complex antibodies. They found patients suffering from depression had antibody positive rates of 78.9%, compared to 24.4% for healthy subjects. These findings suggest mental health and wellness may not only be determined by genes and environment, but also the diverse virome that exists within the human body. The study provides new avenues for research into depression and the role of herpesviruses in mental illness. 

Works Cited: 

[1] N. Kobayashi, et al., Human herpesvirus 6B greatly increases risk of depression by activating hypothalamic-pituitary-adrenal axis during latent phase of infection. iScience 23, 1-37 (2020). doi: /10.1016/j.isci.2020.101187.

[2] Image retrieved from: ​​https://pixabay.com/illustrations/man-window-corona-coronavirus-4957154/