Mechanisms of Entry Into the Central Nervous System by Neuroinvasive Pathogens

Abstract

Background:The literature on neurological manifestations, cerebrospinal fluid analyses, and autopsies in patients with COVID-19 continues to grow. The proposed mechanisms for neurological disease in patients with COVID-19 include indirect processes such as inflammation, microvascular injury, and hypoxic-ischemic damage. An alternate hypothesis suggests direct viral entry of SARS-CoV-2 into the brain and cerebrospinal fluid, given varying reports regarding isolation of viral components from these anatomical sites.Evidence Acquisition:PubMed, Google Scholar databases, and neuroanatomical textbooks were manually searched and reviewed.Results:We provide clinical concepts regarding the mechanisms of viral pathogen invasion in the central nervous system (CNS); advances in our mechanistic understanding of CNS invasion in well-known neurotropic pathogens can aid in understanding how viruses evolve strategies to enter brain parenchyma. We also present the structural components of CNS compartments that influence viral entry, focusing on hematogenous and transneuronal spread, and discuss this evidence as it relates to our understanding of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).Conclusions:Although there is a paucity of data supporting direct viral entry of SARS-CoV-2 in humans, increasing our knowledge of the structural components of CNS compartments that block viral entry and pathways exploited by pathogens is fundamental to preparing clinicians and researchers for what to expect when a novel emerging virus with neurological symptoms establishes infection in the CNS, and how to design therapeutics to mitigate such an infection.

What Can We Still Learn from Brain Autopsies in COVID-19?

“…Similar questions have been raised regarding the infectivity of ophthalmic tissues and optic nerves as a route of CNS entry. 32 SARS-CoV-2 RNA has been variably detected in the cornea, conjunctiva, vitreous, retina, and optic nerves, but with negative IHC and virus isolation, arguing against active infection. [33][34][35][36]…”

The integrative process promoted by EMDR in dissociative disorders: neurobiological mechanisms, psychometric tools, and intervention efficacy on the psychological impact of the COVID-19 pandemic

“…Interestingly, SARS-CoV-2 viral antigens have been detected in the brainstem, where the infected regions included the nucleus of the solitary tract (the main input source for both DMNX and NA in the polyvagal theory) and NA (Li et al, 2020 ), whose myelinated fibers contribute to VVC, health, and social engagement, potentially characterizing COVID-19 as a cardiorespiratory disease (Poli et al, 2020 ). Disrupting the activity of the nucleus of the solitary tract and NA in the brainstem through its neuroinvasive potential (Lahiri et al, 2020 ; Li et al, 2020 ; Yashavantha Rao and Jayabaskaran, 2020 ; Valizadeh et al, 2022 ), SARS-CoV-2 may foster the perturbation of the SES and promote the activation of the cortical regions supporting the emergence of autobiographical EPs, possibly supported by SNS or DVC, and dissociative symptoms.…”

Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status

“…It is still widely debated whether the virus can enter the brain and if the reported neurological symptoms (e.g., fatigue, cognitive impairment, dysosmia) are direct or indirect manifestations of the infection [ 10 , 11 ]. Regardless of the source (i.e., direct or indirect invasion), it has been proposed that brain morphometrical alterations could arise from several factors, such as decreased sensory input (e.g., dysosmia) or chronic inflammation [ 10 , 12 ].…”