Human Herpesvirus 6B Greatly Increases Risk of Depression by Activating Hypothalamic-Pituitary -Adrenal Axis during Latent Phase of Infection

Nobuyuki Kobayashi; Naomi Oka; Mayumi Takahashi; Kazuya Shimada; Azusa Ishii; Yoshitaka Tatebayashi; Masahiro Shigeta; Hiroyuki Yanagisawa; Kazuhiro Kondo

doi:10.1016/j.isci.2020.101187

Human Herpesvirus 6B Greatly Increases Risk of Depression by Activating Hypothalamic-Pituitary -Adrenal Axis during Latent Phase of Infection

iScience. 2020 Jun 26;23(6):101187. doi: 10.1016/j.isci.2020.101187. Epub 2020 May 21.

Authors

Nobuyuki Kobayashi¹, Naomi Oka², Mayumi Takahashi², Kazuya Shimada², Azusa Ishii², Yoshitaka Tatebayashi³, Masahiro Shigeta⁴, Hiroyuki Yanagisawa⁵, Kazuhiro Kondo⁶

Affiliations

¹ Department of Virology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; Department of Psychiatry, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.
² Department of Virology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.
³ Affective Disorders Research Team, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
⁴ Department of Psychiatry, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.
⁵ Department of Public Health & Environmental Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.
⁶ Department of Virology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: kkondo@jikei.ac.jp.

Abstract

Little is known about the effect of latent-phase herpesviruses on their host. Human herpesvirus 6B (HHV-6B) is one of the most ubiquitous herpesviruses, and olfactory astrocytes are one of the most important sites of its latency. Here, we identified SITH-1, an HHV-6B latent protein specifically expressed in astrocytes. Mice induced to produce SITH-1 in their olfactory astrocytes exhibited olfactory bulb apoptosis, a hyper-activated hypothalamic-pituitary-adrenal (HPA) axis and depressive symptoms. The binding of SITH-1 to the host protein calcium-modulating ligand (CAML) to form an activated complex promoted the influx of extracellular calcium. The serum antibody titers for depressive patients with respect to this activated complex were significantly higher than for normal controls (p = 1.78 × 10^-15), when the antibody positive rates were 79.8% and 24.4%, respectively, and the odds ratio was 12.2. These results suggest that, in the latent phase, HHV-6B may be involved in the onset of depression.

Keywords: Behavioral Neuroscience; Molecular Biology; Virology.