Introduction
COVID-19 and its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have left their mark on the early 21st century. Faced with a new pandemic scenario, researchers and scientists around the world were forced to work together to analyze and contain the rapidly spreading disease. This viral pandemic continues to have interconnected effects on a global scale, and its ultimate impact is only beginning to be understood. Beyond the physical and mental strain directly caused by the virus, government measures to contain the spread of the disease, such as social distancing rules, economic blockades, and the fear-inducing and often uncertain flow of information, may have negatively affected people’s well-being. 1 In addition, the unified focus on fighting this pandemic has exhausted scientific and medical resources. As such, the great attention being paid to this newly found pathogen has delayed the scientific and medical management of many other diseases. For example, in the case of the human immunodeficiency virus (HIV), ongoing research has stalled and disruptions have occurred in the medical supply chains and intervention programs needed to contain and treat the disease. 2
Despite the harmful effects of SARS-CoV-2 and the economic, medical, and social measures associated with the pandemic, highly focused research on SARS-CoV-2 has greatly increased the understanding of viruses and their infectious strategies. Countless studies of COVID-19 were conducted and reviews published at an unprecedented rate, allowing for new knowledge and understanding of human virus interactions.3,4.
An emerging but still largely ignored aspect of viral infections are their associated long-term neurological/neuropsychiatric symptoms, which can manifest as both neurological disease and psychopathological expression. SARS-CoV-2 has recently revived the focus on the dangers associated with persistent infection after recovery from illness.6,7 Long-term neuropsychiatric symptoms following viral infection are well-known phenomena that have been documented and thoroughly studied in diseases such as HIV. -1,8 Herpes simplex virus 1 (HSV-1)9 and recently Ebola virus disease (EVD).10,11
Common viral strategies for systemic infection and neuroinvasion: primary effects of viral activity
Neuroinvasion of the central nervous system (CNS) and the ability of viruses to “hide” in structures residing in the CNS may be a major cause of subliminal infection and persistent disease. Given the poorly accessible nature of CNS cells behind the blood-brain barrier (BBB) and their cytolytic sensitivity, neuronal cells may provide an ideal protective environment that supports reservoirs of persistent viral replication and latency.12 ,13 To exploit this protective niche, viruses have been suggested to use several pathways of neuroinvasion. HIV-1, for example, targets immune cells, such as lymphocytes (eg, CD4+ T cells) and monocytes (eg, macrophages and dendritic cells) that express a high surface density of CD4 receptors, which viruses can use to facilitate transport across the BBB as a direct entry route.13,14 CD4-expressing immune cells in the brain, such as astrocytes, pericytes, and microglia, they can be recruited and subsequently harbor the viral genome within the CNS.14–16 Protected by the BBB, the viral genome can silently replicate in microglia and other CNS-resident structures, thereby expanding viral reservoirs and causing a persistent deep structural infection and neuronal dysfunction.12,14 This phenomenon of latent infection and reactivation has been extensively studied in HIV-1, thus providing a potential explanation for the chronicity of infection and associated cognitive symptoms despite therapy an thyretroviral.8,12.
Similar neurotropic features are increasingly being described for other viruses, such as HSV-1,17 EVD,18 and members of the coronavirus family, such as murine hepatitis virus, Oriental respiratory syndrome coronavirus Medium (MERS-CoV) and SARS-CoV-. 2.7,19,20 For example, in vitro analysis of infected human organoids has revealed the expression of angiotensin-converting enzyme 2 (ACE2), the major receptor of SARS-CoV-2, in resident macrophages lymph nodes,21 multiple brains. areas and resident glial cells in the CNS, such as astrocytes, supporting similar mechanisms of neurovirulence through these viruses.22 Although the presence of these neuroinvasive pathways is inconclusive for many viruses, secondary infection of the CNS through virus-induced loss of BBB integrity with elevated CNS. The entry of inflammatory molecules and viral particles has been widely accepted.23,24 Thus, subsequent cytokine storms and associated systemic inflammation lead to multiple organ damage, cardiac dysfunction, and CNS inflammation may be a major guilty of interoceptive alteration and cognitive malfunction (Figure 1).25
Figure 1 Virus-induced enhancement of blood-brain barrier immune cell trafficking. The figure illustrates how a viral infection of organs can stimulate the trafficking of white blood cells (eg, macrophages) and chemicals across the BBB. (1) For example, SARS-CoV-2 infection in the periphery (i.e., lung/gut) appears to generate an inflammatory microenvironment, releasing increased levels of activated immune cells that can travel to the brain, disrupting the integrity endothelial and inducing a similar inflammatory phenomenon there. (2) Increased macrophage excitation, immune cell numbers, and stimulated cytokine release cause this endothelial disruption, diminishing the brain’s immune privilege. (3) Enhanced trafficking of uninfected and possibly infected macrophages may also facilitate the transport of viral particles into the brain, thereby altering microglia and astrocyte homeostasis, building viral reservoirs, and affecting cellular interaction. (4) Infection-induced cytokine storms in the brain may further aid viral replication by damaging the host’s DNA, stimulating an even greater rate of RNA polymerase errors, and thereby increasing levels of mutation, causing a systemic and persistent infection. We hypothesize that this infection-stimulated inflammatory neuronal environment directly or indirectly alters mitochondrial function by requiring increased levels of metabolic substrates (eg, oxygen and glucose) to maintain normal functionality, thus competing with normal neuronal energy demands . As a result, stress-induced viral reactivation and subsequent induction of HIF-1a and mitochondrial ROS can lead to abnormal generation and distribution of metabolites, for example, in the form of increased mitochondrial GABA retention and accumulation of extracellular or cytoplasmic glutamate, causing a functional disturbance of brain networks and interruption in cognitive processing.
Based on these findings, we suggest that many viruses have shared neurovirulence and CNS persistence potential, despite fundamental differences in their specific targeting and immune responses, and that viral latency and chronic CNS inflammation are the likely causes, in part, of Specifically, we propose that viral latency and reactivation in infected cells harbored by the CNS hijack cellular reproductive machinery and energy expenditure and have deleterious effects on host DNA, metabolic tone and cellular communication, activation and proliferation.7, 27–29 Viral interference in metabolic regulatory processes can directly alter intercellular communication and the composition of the extracellular microenvironment, thus exerting multiple effects on phenotypic expression of the host and viral replication.27,30,31 This dysregulated metabolite generation has been demonstrated in latent HIV. -1 infection, in which Russian wine stress-induced reactivation is associated with upregulated glycolysis32 and induction of hypoxia-inducible factor 1a (HIF-1a) and mitochondrial reactive oxygen species (ROS) .33,34 These state-dependent changes in metabolic processing in infected and neighboring cells, and the subsequent. Alterations in metabolite generation, such as increased mitochondrial ROS, gamma aminobutyric acid (GABA) retention, and glutamate excitotoxicity, may therefore be responsible for the functional disturbance of brain networks and cognitive disruption depending on the phase of viral infection.35–38. may represent a conserved evolutionary strategy given its reservoir of heteroplasmic information.39 Thus, viruses, including SARS-CoV-2, exhibit extensive artificial intelligence processes, which allow, for example, mitochondrial sequestration.40
Common neuropsychiatric sequelae of viral infection: secondary effects of viral activity
Interestingly, the neurological or neuropsychiatric effects induced by viruses are similar between viruses.26 Often, the sequelae of virus infections suggest that they are neurovirulent, such as HIV-1, HSV-1, EVD, MERS-CoV, and SARS- CoV-2— have been reported to include encephalopathies (eg, meningitis or encephalitis, seizures, and strokes) with altered mental status; brain fog; fatigue; and increased neuropsychiatric incidence of anxiety, depression and post-traumatic stress (Table 1).5,9,11,41-43. The significance level for the data presented below is p < 0.05.
Table 1 Neuropsychiatric disorders associated with viral infections
Notably, a recent follow-up study of 197 EVD survivors two years after their discharge from the Ebola treatment center reported a prevalence of anxiety, depression, and posttraumatic stress disorder (PTSD) of (n = 49, 24.9%), (n = 93, 47.2%) and (n = 43, 21.8%), respectively, with older survivors (≥30 years) demonstrating a greater likelihood of developing anxiety (AOR = 3.04, 95% CI 1.2–7.7; p = 0.019) and depression (AOR = 8.5, 95% CI 2.68–27.01; p = 0.001 ) compared to younger survivors (<30 years).11…