Immuno-Genetic, Inflammation, retro-Virus, Environnement : from etiopathogeny of major psychoses to animal models – I-GIVE

Mental illness is a major public health burden worldwide needing urgent research actions. Bipolar disorder (BD) in particular, is known to be associated with substantial functional impairment, high health care costs, stigmatization and is the 4th cause of disability-adjusted life-years worldwide of all brain disorders.
Immunology combined to neurobiology now offer prominent tools to yield biomarkers, so far missing in psychiatry, and to design innovative treatment approaches based on the discovery of new molecular and cellular targets. Thus the project I-GIVE will combine multidisciplinary approaches (clinical, viral, immunological, genetic, bioinformatics and analysis of a pre-clinical animal model) to explore a global hypothesis placing the Human Endogenous Retro-Virus, HERV-W, at the crossroads between susceptibility to environmental factors (such as winter-spring births, infections, urbanicity…) and genetic factors controlling immune responses (innate and adaptive immunogenetics) as BP are now known to be significantly associated with neuro-inflammation.
Previously, we and others have demonstrated that, after reactivation by environmental factors, Human Endogenous Retroviruses type “W” family (HERV-W) envelope gene encodes a pro-inflammatory and neurotoxic protein (Env). In BD, we have reported preliminary data showing the presence of HERV-W Env abnormal expression, associated with infectious stigmas, possibly related to the chronic inflammatory and neurotoxic state likely involved in acute mood episodes and consequent slow progressive neurobiological impairments.
The project I-GIVE aims to obtain a proof of concept of the involvement of HER-W in BD. This project gathers the internationally recognized expertise of 5 partners in the field of immunogenetics/immunology, endogenous retrovirology, clinical research in psychiatry, bioinformatics and of cutting-edge molecular imaging in neuroscience. Noticeably, HER-W discoverer will also participate in this project. I-GIVE multidisciplinary project will: 1) assess the HERV-W levels in stabilized and acutely ill BD patients, 2) measure the systemic associated immuno-inflammatory cascade in BD patients at different stages, 3) identify clinical characteristics of patients according to HERV-W expression and immuno-inflammatory profiles, 4) explore gene x environment interactions that may modulate the immuno-inflammatory response, and 5) use transgenic HERV-W ENV mice to elucidate the underlying molecular mechanisms of neuronal dysfunctions. “Psy-Coh” Cohort, labelled by “Investissements d’Avenir” programme, will be a core element for patient enrolment and assessment.
Thus I-GIVE will allow identification of new biomarkers and their correlation with clinical profiles and immuno-inflammatory/immuno-genetic markers, and description of patho-physiological mechanisms of a psychiatric disorder. In addition, I-GIVE should help to design innovative treatments and foster personalized psychiatry tailored to the needs of each patient. Notably, monoclonal antibodies anti-HERV-W Env will be assessed in a preclinical model for their ability to slow, stop, or even reverse the progression of the psychosis in patients. I-GIVE project should thus lead to major results that will have strong impacts on the scientific community, pharmaceutical industries and, in a longer term, on improvement of BD patients and their family.