Viral Infections and Mechanisms of Illness in Psychotic Disorders
This summary is based on the talk by Prof Ian Everall. Professor Everall has been at the forefront of research into cellular, molecular and genetic changes in the brain in major psychiatric disorders for over twenty years.
There is growing evidence that Human Endogenous Retroviruses (HERVs) may be associated with schizophrenia.[Perron et al. 2008]
Viral infections can increase the expression of HERVs and studies indicate the HERV-W and HERV-K families are of particular interest. HERVs comprise 8% of human DNA and can be passed to subsequent generations.
- HERV-K is an enhancer for the schizophrenia-linked gene PRODH – proline dehydrogenase 1, which is located on chromosome 22q11.21, a region associated with the contiguous gene deletion syndromes such as DiGeorge syndrome. Mutations in PRODH are linked with susceptibility to schizophrenia 4 (SCZD4). HERV-W transcript is found to be significantly elevated in the brain in schizophrenia with Env and Gag proteins found in up to 50% of plasma samples in schizophrenia.[Perron et al. 2008]
- Studies show that altered levels of tumour necrosis factor-α (TNF-α) may be associated with major depressive disorder (MDD) and results support the idea that modifications in the pro-inflammatory pathways (post-infection host immune response) could be involved.[Dean et al. 2010]
- Increased levels of transmembrane TNF are reported in Brodmann’s area 46 but not 24 in MDD, in Brodmann’s area 24 but not 46 in bipolar disorder, but remain unchanged in schizophrenia. Other TNF-α markers show differential changes in the cortex for MDD, bipolar disorder, and schizophrenia which may be unrelated to classical inflammation.[Dean et al. 2013]
- Many studies have provided insight into the molecular mechanisms of schizophrenia, but it is generally unknown which genes or pathways are affected.[Rock et al. 1994, Lilienbaum. 2013]
- Gene expression studies have identified genes in the ubiquitin-proteasome system (UPS) as possible biomarkers in psychotic disorders. This system participates in or regulates numerous cellular processes, such as selective protein degradation, cell cycle progression, apoptosis, signal transduction, transcriptional regulation, receptor control by endocytosis, immune response and the processing of antigens. The UPS is involved in the replication of certain viruses (e.g Hepatitis B Virus).
- Viruses can manipulate the ubiquitin system to favour their propagation by redirecting cellular ubiquitin enzymes or encoding their own ubiquitin components to enable replication and immune evasion. [Randow F & Lehner P, 2009]
- Gene ontology analyses revealed the top categories as ubiquitination, neurotransmitter transport, and energy metabolism,[Mistry et al. 2013] with a 5-fold increase in S100 calcium-binding protein A8 (S100A8) in schizophrenia.[Pérez-Santiago et al. 2012]
- Another study demonstrated that UPS-related genes were more prominent in the dorsolateral prefrontal cortex layer 5 in schizophrenia, but less so in schizoaffective disorder.[Arion et al. 2015]
- A relationship between positive psychotic symptoms and UPS genes is inferred,[Bousman et al. 2010] and UPS activity is regulated by many components currently being researched, some of which regulate dopamine synthesis.
- COVID-19 caused by the SARS-CoV-2 (Beta coronavirus) which is an RNA virus has been shown to be neurotropic and neuroinvasive. It is associated with a range of neuropsychiatric manifestations. We cover the details in the article on neuropsychiatric manifestations of SARS-CoV-2 brain involvement.