An image of Purkinje cells in the cerebellum
Confocal microscope image of cerebellar Purkinje cells.  They have been stained with tdTomato, which causes them to appear golden!  Image courtesy of National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (BrainsRusDC – Own work).

Does Herpes Virus Cause Mood Disorders?

Photograph of Dr Bhupesh K Prusty
Dr Bhupesh K Prusty, from the Department of Microbiology, University of Würzburg.

New research published in Frontiers in Microbiology shows remarkable links between herpes virus infection and mood disorders.  Dr Bhupesh Prusty and his team conducted post-mortem brain biopsies on people who had suffered from bipolar mood disorder (BMD), major depressive disorder (MDD), schizophrenia, and on control patients with no history of psychiatric illness.  They found that markers of herpes virus infection were detected more frequently in the brains of MDD and BMD sufferers, compared to schizophrenics and controls.

It has been previously established that childhood hospitalisation for infection, whether viral or nonviral, is associated with an increased risk of developing schizophrenia, MDD and BMD.  Why should this be the case? Does herpes provide clues about the underlying microbiology?

Inflammation and Depression

There is an increasing amount of evidence that shows a relationship between inflammation and depression.  For example, plasma concentrations of cytokines that stimulate inflammation, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor (TNF), are increased in depressed patients.  The antidepressant, fluoxetine, has been shown to reduce interleukin-6 levels in the serum of depressed patients.  Interestingly, depressed patients who do not respond to selective serotonin reuptake inhibitors (SSRIs), the most common type of antidepressant, continue to demonstrate raised IL-6 levels after commencement of treatment.  Increased levels of IL-1, IL-6 and TNF have also been reported in BMD.

It is interesting to recognise that the behaviour of depressed patients is very similar to the sickness behaviour of patients with acute infection.  Both groups show alterations in sleep cycle, changes in appetite, hightened sensitivity to pain, irritability, reduced sexual activity, and reduced interest in getting out (exploratory behaviour).  Even the cognitive changes, such as impaired concentration, poor short-term memory and executive dysfunction, are similar.

One interesting proposition is a biological pathway that would provide a link between inflammation and mood disorders.  One such possibility may be the role of indoleamine 2,3-dioxygenase (IDO), which is present in immune cells, including microglia in the brain, and which is ubiquitous throughout the organs of the body.  IDO is increased in animals with sickness behaviour.  Furthermore, IDO knockout mice do not manifest sickness behaviour in the face of immunological challenge.  IDO activation and inflammation could cause depression by tryptophan depletion or by kynurenine toxicity.

Roseoloviruses

Of course, there are multiple factors that might cause inflammation in the brain, but viral infections are one of the most common causes.  Prusty et al focused on a very common type of virus that infects a large percentage of the human population, the roseolovirus genus.  Specifically, they investigated two forms of the human herpes virus (HHV), HHV-6A and HHV-6B.  There are more than a 130 types of herpes virus, of which nine infect humans.  More than 90% of people have been infected with at least one of these herpesviruses.  As is the case with viruses, a latent form remains in most people with the potential for reactivation.  Roseoloviruses have a tissue tropism for immune cells, such as T cells, B cells, natural killer cells, monocytes and macrophages.  They are transmitted by respiratory contact (and not sexual contact).

Image showing HHV-6
An electron micrograph of HHV-6. The image also includes a labelled insert of the mature virus particle. HHV-6 is a double stranded DNA virus of the herpes family.

The Cerebellum in Mood Disorders

Dr Prusty chose to investigate the cerebellum, in the main because animal studies had shown that perinatal viral infection was associated with long-term anatomical changes in the cerebellum and behavioural disturbances in adult animals.  Of relevance to this work, cerebellar dysfunction has been associated with a number of psychiatric conditions, autism being perhaps the best-known.  We know that corticocerebellar tracts are abnormal in schizophrenia, and that the cerebellum tends to be a bit smaller in patients with MDD and in BMD.

Functional connectivity in healthy and depressed geriatrics. Cerebellar seed region shown in the bottom row. Cortico-cerebellar connectivity is significantly worse in depressed subjects.

The images above (from Alalade et al.) show reduced cortico-cerebellar connectivity in depressed geriatrics, compared to healthy geriatrics.  The seed region for the connectivity trace is shown in the bottom row.  Compare especially the leftmost and middle columns and notice that there is almost no frontal connectivity in the depressed group.

Herpes, the Cerebellum and Mood Disorders

Prusty et al investigated the presence of late proteins, which are formed after replication of a virus.  Late proteins are therefore a marker of active infection.  They were able to detect signs of active HHV-6A and HHV-6B infection in the Purkinje cells of the cerebellum in MDD and BMD cadavers, particularly at the interface of the granule cell and molecular layers.  Compared to controls, statistical significance was greatest in the MDD group, slightly less in the BMD group, and absent in the schizophrenic group.  Additionally, there was occasional staining of GABAergic interneurons of the molecular layer, and astrocytes and microglia in the vicinity of positively stained Purkinje cells.  These results provide unambiguous evidence for a strong and specific effect of herpes virus, HHV-6 in particular, on Purkinje nerve fibres.

So, does herpes cause MDD and BMD?  No, not directly at least, but via the effects of inflammation on brain function, herpes is setting the scene for depression.  It would seem that perinatal HHV-6 infection is the first step.  In adulthood, reactivation of latent HHV-6 sets in motion inflammation that may lead to MDD and BMD.  Whether this requires an emotional trigger or not requires clarification.  Some patients are unable to identify an obvious emotional cause of their depression and perhaps their illness is entirely biological and without a psychological cause.

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