Interoception, Trait Anxiety, and the Gut Microbiome: A Cognitive and Physiological Model - Article abstract #931962

Long COVID, in which disease-related symptoms persist for months after recovery, has led to a revival of the discussion of whether neuropsychiatric long-term symptoms after viral infections indeed result from virulent activity or are purely psychological phenomena. In this review, we demonstrate that, despite showing differences in structure and targeting, many viruses have highly similar neuropsychiatric effects on the host. Herein, we compare severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus 1 (HIV-1), Ebola virus disease (EVD), and herpes simplex virus 1 (HSV-1). We provide evidence that the mutual symptoms of acute and long-term anxiety, depression and post-traumatic stress among these viral infections are likely to result from primary viral activity, thus suggesting that these viruses share neuroinvasive strategies in common. Moreover, it appears that secondary induced environmental stress can lead to the emergence of psychopathologies and increased susceptibility to viral (re)infection in infected individuals. We hypothesize that a positive feedback loop of virus-environment-reinforced systemic responses exists. It is surmised that this cycle of primary virulent activity and secondary stress-induced reactivation, may be detrimental to infected individuals by maintaining and reinforcing the host’s immunocompromised state of chronic inflammation, immunological strain, and maladaptive central-nervous-system activity. We propose that this state can lead to perturbed cognitive processing and promote aversive learning, which may manifest as acute, long-term neuropsychiatric illness.

During the COVID-19 pandemic, research on the relationships between the virus and its human host has become fundamental to understand this pathology and its effects. Attaining this profound understanding is critical for the effective containment and treatment of infections caused by the virus. In this review, we present some possible mechanisms by which psychopathological symptoms emerge following viral infections of the central nervous system (CNS). These proposed mechanisms are based on microbial communication and the induced priming of microglial antibody activation within the CNS through Toll-like receptor signaling. In this process, chronic microglial activation causes increased glutamate release in virally-altered, high-density neuronal structures, thereby modulating cognitive networks and information integration processes. This modulation, in turn, we suggest, affects the accuracy of sensory integration and connectivity of major control networks, such as the default mode network. The chronic activation of immunological responses and neurochemical shifts toward an elevated glutamate/gamma-aminobutyric acid ratio lead to negative reinforcement learning and suboptimal organismic functioning, for example, maintaining the body in an anxious state, which can later become internalized as trait anxiety. Therefore, we hypothesize that the homeostatic relationship between host, microbiome, and virome, would be decisive in determining the efficiency of subsequent immunological responses, disease susceptibility, and long-term psychopathological effects of diseases that impact the CNS, such as the COVID-19.

Mitochondria, the cellular powerhouses with bacterial evolutionary origins, play a pivotal role in maintaining neuronal function and cognitive health. Several viruses have developed sophisticated mechanisms to target and disrupt mitochondrial function which contribute to cognitive decline and neurodegeneration. The interplay between viruses and mitochondria might be traced to their co-evolutionary history with bacteria and may reflect ancient interactions that have shaped modern mitochondrial biology.

Prion’ is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria. Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation. Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequenct production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manesfestions post-acute viral infection.

Artificial Intelligence (AI), which is the general term used to describe technology that simulates human cognition