Viruses and psychiatric disorders: We have not crossed the borderline from hypothesis to proof yet (Review)

Abstract

Most psychiatric disorders are heterogeneous and are attributed to the synergistic action of a multitude of factors. It is generally accepted that psychiatric disorders are the outcome of interactions between genetic predisposition and environmental perturbations, which involve psychosocial stress, or alterations in the physiological state of the organism. A number of hypotheses have been presented on such environmental influences that may include direct insults such as injury, malnutrition and hostile living conditions, or indirect sequelae following infection from viruses such as influenza, arboviruses, enteroviruses and several herpesviruses, or the differential expression of human endogenous retroviruses. It is known that the concept of viruses is far more extensive than their perception as mere agents of acute infections, or chronic debilitating diseases, such as AIDS or some forms of cancer. Notably, an apparent causal connection between viruses and the pathophysiology of diseases has been suggested; however, it remains unclear as to how to establish this causal connection. There are inherent difficulties in answering this question with certainty, which may be due to the multitude of genetic and environmental influences that can lead to psychopathology; the latent state of chronic infection exhibited by a number of neurotropic viruses; the late onset of psychiatric disorders with respect to the acute phase of viral infection at which detection tests would be successful; the complexity of the virome; and the existence of thousands of viral species. The present review aims to provide an outline of the conclusions that have thus far been reached regarding a possible association between viral infection and psychiatric disease, and the obstacles confronted during the quest for the truth behind the role of viruses.

Keywords: endogenous retroviruses; psychiatric disease; schizophrenia; virome; viruses.

Figure 1.

Diagrammatic depiction of viruses and their relationship with the human host. Novel molecular techniques and sequencing technologies have enabled the understanding that humans not only live alongside a considerable number of viruses, but also that diverse populations of viruses (collectively termed the virome) reside within the human body and may influence both physiology and disease, although substantial evidence about the association of viruses with psychiatric and numerous other diseases is still lacking. The concept of the virome constitutes fundamental proof that a small proportion of viruses cause disease. A viral infection usually leads to a symbiotic state within the host, but parasitic states that lead to disease still occur, with serious consequences for the host either during an acute, or a chronic latent phase of infection. Moreover, part of the human genome consists of integrated sequences of retroviral origin and partial expression of the endogenous retrovirus genes has been linked to human physiology and, if aberrantly expressed, to disease. Created in https://BioRender.com.

Figure 2.

Outline of the different factors that may lead to the development of mental illness. Types of pathophysiological pathways in which viral infection may tentatively contribute to a psychiatric disease are also shown, despite this we still have not crossed the borderline from hypothesis to proof yet. Created in https://BioRender.com. CNS, central nervous system.

Figure 3.

Diagrammatic presentation of viral-induced neuroinflammation, following either a systemic, or a direct CNS infection. Viruses that gain entry to the host through the circulatory, respiratory and the gastrointestinal routes, can still elicit neuroinflammation. Initial inflammatory events may lead to the release of proinflammatory cytokines and chemokines that can disrupt the integrity of the BBB, thus rendering it permeable to viral particles, toxins and infected immune cells. Alternatively, viruses such as α-herpesviruses and rhabdoviruses invade the CNS directly through spread within neuronal axons. In both cases, astrocytes and microglia constitute the main immune mediators within the CNS and their activation via Toll-like receptors generate further production of proinflammatory cytokines, leading to neuroinflammation in the brain. Created in https://BioRender.com. BBB, blood-brain barrier; CNS, central nervous system.