Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

B cells going viral in the CNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis.

A diverse number of DNA and RNA viruses have the potential to invade the central nervous system (CNS), causing inflammation and injury to cells that have a limited capacity for repair and regeneration. While rare, viral encephalitis in humans is often fatal and survivors commonly suffer from permanent neurological sequelae including seizures. Established treatment options are extremely limited, predominantly relying on vaccines, antivirals, or supportive care. Many viral CNS infections are characterized by the presence of antiviral antibodies in the cerebral spinal fluid (CSF), indicating local maintenance of protective antibody secreting cells. However, the mechanisms maintaining these humoral responses are poorly characterized. Furthermore, while both viral and autoimmune encephalitis are associated with the recruitment of diverse B cell subsets to the CNS, their protective and pathogenic roles aside from antibody production are just beginning to be understood. This review will focus on the relevance of B cell responses to viral CNS infections, with an emphasis on the importance of intrathecal immunity and the potential contribution to autoimmunity. Specifically, it will summarize the newest data characterizing B cell activation, differentiation, migration, and localization in clinical samples as well as experimental models of acute and persistent viral encephalitis.

Coronavirus Disease 2019 (COVID-19) and Its Neuroinvasive Capacity: Is It Time for Melatonin?

The world faces an exceptional new public health concern caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), subsequently termed the coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO). Although the clinical symptoms mostly have been characterized, the scientific community still doesn´t know how SARS-CoV-2 successfully reaches and spreads throughout the central nervous system (CNS) inducing brain damage. The recent detection of SARS-CoV-2 in the cerebrospinal fluid (CSF) and in frontal lobe sections from postmortem examination has confirmed the presence of the virus in neural tissue. This finding reveals a new direction in the search for a neurotherapeutic strategy in the COVID-19 patients with underlying diseases. Here, we discuss the COVID-19 outbreak in a neuroinvasiveness context and suggest the therapeutic use of high doses of melatonin, which may favorably modulate the immune response and neuroinflammation caused by SARS-CoV-2. However, clinical trials elucidating the efficacy of melatonin in the prevention and clinical management in the COVID-19 patients should be actively encouraged.

Age-related changes in the inflammatory responses to viral infections in the central nervous system during childhood.

BACKGROUND: The developmental stages and function of immune cells in the central nervous system during infancy and childhood are poorly understood. We analyzed whether cytokine and chemokine profiles in children and adolescents with viral central nervous system infections were different depending on age. METHODS: The acute phase cerebrospinal fluid of 80 children (mean age 98 months, range 1-206 months) were analyzed for protein levels of interleukin-1ß (IL-1ß), IL-1-RA, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, monocyte chemoattractant protein-1 (MCP-1), interferon (IFN) gamma-induced protein 10 (IP-10), IFN-γ, and macrophage migration inhibitory factor (MIF). RESULTS: We found an age-dependent increased expression of IL-4, IL-6, IL-13, MIF, IP-10, and IFN-γ and a decreased expression of MCP-1 and IL-15 in response to a viral infection of the central nervous system. In contrast, all other cytokines and chemokine were unaffected by the age of the patient. CONCLUSION: These findings demonstrate that the immunological response to a viral infection matures during childhood and adolescence. This may in turn be of importance for the outcome of a viral infection and the risk for subsequent sequela. It also demonstrates that age is a factor that needs to be considered when using cytokines and chemokines as biomarkers for infections in the central nervous system. IMPACT: The immunological response to a viral infection matures during childhood and adolescence. This may be of importance for the outcome of a viral infection and the risk for subsequent sequela. It also demonstrates that age is a factor that needs to be considered when using cytokines and chemokines as biomarkers for infections in the central nervous system.

Prolonged activation of cytomegalovirus early gene e1-promoter exclusively in neurons during infection of the developing cerebrum.

The brain is the major target of congenital cytomegalovirus (CMV) infection. It is possible that neuron disorder in the developing brain is a critical factor in the development of neuropsychiatric diseases in later life. Previous studies using mouse model of murine CMV (MCMV) infection demonstrated that the viral early antigen (E1 as a product of e1 gene) persists in the postnatal neurons of the hippocampus (HP) and cerebral cortex (CX) after the disappearance of lytic infection from non-neuronal cells in the periventricular (PV) region. Furthermore, neuron-specific activation of the MCMV-e1-promoter (e1-pro) was found in the cerebrum of transgenic mice carrying the e1-pro-lacZ reporter construct. In this study, in order to elucidate the mechanisms of e1-pro activation in cerebral neurons during actual MCMV infection, we have generated the recombinant MCMV (rMCMV) carrying long e1-pro1373- or short e1-pro448-EGFP reporter constructs. The length of the former, 1373 nucleotides (nt), is similar to that of transgenic mice. rMCMVs and wild type MCMV did not significantly differed in terms of viral replication or E1 expression. rMCMV-infected mouse embryonic fibroblasts showed lytic infection and activation of both promoters, while virus-infected cerebral neurons in primary neuronal cultures demonstrated the non-lytic and persistent infection as well as the activation of e1-pro-1373, but not -448. In the rMCMV-infected postnatal cerebrum, lytic infection and the activation of both promoters were found in non-neuronal cells of the PV region until postnatal 8 days (P8), but these disappeared at P12, while the activation of e1-pro-1373, but not -448 appeared in HP and CX neurons at P8 and were prolonged exclusively in these neurons at P12, with preservation of the neuronal morphology. Therefore, e1-pro-448 is sufficient to activate E1 expression in non-neuronal cells, however, the upstream sequence from nt -449 to -1373 in e1-pro-1373 is supposed to work as an enhancer necessary for the neuron-specific activation of e1-pro, particularly around the second postnatal week. This unique activation of e1-pro in developing cerebral neurons may be an important factor in the neurodevelopmental disorders induced by congenital CMV infection.

Does coronaviruses induce neurodegenerative diseases? A systematic review on the neurotropism and neuroinvasion of SARS-CoV-2.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in 2019 in Wuhan, China. Clinically, respiratory tract symptoms as well as other organs disorders are observed in patients positively diagnosed coronavirus disease 2019 (COVID-19). In addition, neurological symptoms, mainly anosmia, ageusia and headache were observed in many patients. Once in the central nervous system (CNS), the SARS-CoV-2 can reside either in a quiescent latent state, or eventually in actively state leading to severe acute encephalitis, characterized by neuroinflammation and prolonged neuroimmune activation. SRAS-CoV-2 requires angiotensin-converting enzyme 2 (ACE2) as a cell entry receptor. The expression of this receptor in endothelial cells of blood-brain barrier (BBB) shows that SRAS-CoV-2 may have higher neuroinvasive potential compared to known coronaviruses. This review summarizes available information regarding the impact of SRAS-CoV-2 in the brain and tended to identify its potential pathways of neuroinvasion. We offer also an understanding of the long-term impact of latently form of SARS-CoV-2 on the development of neurodegenerative disorders. As a conclusion, the persistent infection of SRAS-CoV-2 in the brain could be involved on human neurodegenerative diseases that evolve a gradual process, perhapes, over several decades.

Adenovirus Infection-associated Central Nervous System Disease in Children.

BACKGROUND: Adenovirus (Adv) is a frequent etiology of acute respiratory tract infections. Although rare, neurologic manifestations are known to occur during Adv infection. METHODS: We retrospectively analyzed clinical, laboratory, outcome and the relationship between clinical characteristics and viral detection results in the cerebrospinal fluid (CSF) in children with Adv-associated central nervous system (CNS) dysfunction. RESULTS TWENTYONE: (1.5%) cases had Adv-associated CNS manifestations. The median age was 1.4 years and 20 (95%) were less than 5 years of age. Six (28%) were male. The most frequently cited CNS symptoms were altered consciousness (100%) and seizure (14.3%). Fourteen cases (73.7%) had abnormal electroencephalogram examination and 6 cases (37.5%) had abnormal imaging. None of the patients had received cidofovir administration. Twenty children recovered without sequelae and 1 patient died of respiratory failure. Patients with positive Adv polymerase chain reaction (n = 11) presented lower onset age compared with that of patients with negative Adv polymerase chain reaction (n = 10) in the CSF. Clinical manifestation, laboratory findings, imaging studies and electroencephalogram showed no significant difference between the 2 groups. CONCLUSION: Adv is a rare cause of CNS disease in children, mainly causing altered consciousness. Adv was detected in more cases in the respiratory tract than the CSF, but the majority of patients had the virus detected in both. The lack of Adv in the CSF does not exclude CNS involvement. Furthermore, the viral detection results in the CSF do not seem useful as an indicator of the severity of CNS disease.

Acute flaccid myelitis outbreak through 2016-2018: A multicenter experience from Turkey.

AIM: We aim to describe the demographic characteristics, etiology, neurophysiology, imaging findings, treatment, prognosis, and prognostic factors of acute flaccid myelitis. METHODS: The clinical data, laboratory test and, magnetic resonance imaging (MRI) results of pediatric patients diagnosed with acute flaccid myelitis according to the Centers for Disease Control criteria between August 1, 2016, and December 31, 2018, from 13 centers in Turkey were reviewed. RESULTS: Of the 34 cases identified, 31 were confirmed (91.2%). Eighteen patients (55.9%) were boys. The median patient age was 4 years (interquartile range 2.5-6.9 years). Most of the patients were admitted in 2018 (n = 27). A preceding history of a febrile illness was reported in all patients, with a median of 4 days (interquartile range 3-7 days) before symptom onset. Thirty-one patients had T2 hyperintensity on spinal MRI, and 18 patients had cerebrospinal fluid pleocytosis. The most common infectious agents were entero/rhinoviruses (n = 5) in respiratory specimens. All patients except one received immunotherapy either alone or in combination. Among 27 patients with follow-up data 24 had persistent weakness. Involvement of four limbs together with an abnormal brain MRI at onset were associated with a poor prognosis. CONCLUSION: The number of patients with acute flaccid myelitis increased since 2012, spiking with every 2-year interval, largely in the pediatric population. The median age decreases with every outbreak. Clinicians should be aware of the clinical picture for early collection of specimens and early start of rehabilitation programs. Further studies are needed to better characterize the etiology, pathogenesis, risk factors, and treatment of this rare condition.

A novel interspecies recombinant enterovirus (Enterovirus A120) isolated from a case of acute flaccid paralysis in China.

EV-A120 is a recently identified serotype of the enterovirus A species. Only one full-length genomic sequence is currently available in GenBank, and very few studies have been conducted on EV-A120 globally. Thus, additional information and research on EV-A120 are needed to explore its genetic characteristics, phylogeny, and relationship with enteroviral disease. In this study, we report the phylogenetic characteristics of a EV-A120 strain (Q0082/XZ/CHN/2000) from Tibet, China. The amino acid sequence similarity and nucleotide sequence similarity of the full-length genomic sequence of this EV-A120 strain and the EV-A120 prototype strain were 96.3% and 79.9%, respectively, showing an evolutionary trend. Recombination analysis found intraspecies recombination in the 5' -UTR, 2B, 2C, and 3D regions. Serum neutralization testing of the EV-A120 (Q0082) strain was also carried out. Low serum-positive rates and geometric mean titres (GMTs) indicated that the extent of EV-A120 transmission and exposure in the population was very limited compared with that in the outbreaks of EV-A71 and CV-A16 in China since 2008. The EV-A120 strain (Q0082) is non-temperature sensitive, indicating its potential to spread in the population. In summary, this study reports the full-length genomic sequence of EV-A120 and provides important information for its global molecular epidemiology.

Stroke as a complication and prognostic factor of COVID-19. / Ictus como complicación y como factor pronóstico de COVID-19.

INTRODUCTION: Contradictory data have been reported on the incidence of stroke in patients with COVID-19 and the risk of SARS-CoV-2 infection among patients with history of stroke. METHODS: This study systematically reviews case series reporting stroke as a complication of COVID-19, and analyses the prognosis of patients with COVID-19 and history of stroke. The pathophysiological mechanisms of stroke in patients with COVID-19 are also reviewed. CONCLUSIONS: History of stroke increases the risk of death due to COVID-19 by 3 times. Stroke currently seems not to be one of the main complications of COVID-19.

Acute Flaccid Myelitis With Neuroradiological Finding of Brachial Plexus Swelling.

BACKGROUND: Acute flaccid myelitis is a recently defined clinically distinct syndrome of polio-like acute flaccid paralysis. Acute flaccid myelitis cases show characteristic neuroradiological features of longitudinal spinal cord lesions with predominant gray matter involvement. Current evidence suggests injury to the anterior horn neurons as the underlying mechanism. METHODS: We describe three patients with acute flaccid myelitis who developed flaccid upper limb weakness with diminished deep tendon reflexes after prodromal fever. Spinal magnetic resonance imaging (MRI) (axial and sagittal T1- and T2-weighted sequences) and brachial plexus MRI (coronal short tau inversion recovery sequence) at the acute stage were performed. RESULTS: Spinal MRI showed extensive longitudinal lesion in the spinal cord with predominant gray matter involvement. We were able to demonstrate concurrent swelling and hyperintensity in the brachial plexus in all the three patients at the acute stage. CONCLUSION: The coexisting signal intensities suggest an extension of acute flaccid myelitis pathology to the brachial plexus, highlighting the possible peripheral nerve involvement in acute flaccid myelitis.

Molecular and Histologic Diagnosis of Central Nervous System Infections.

Infections of the central nervous system cause significant morbidity and mortality in immunocompetent and immunocompromised individuals. A wide variety of microorganisms can cause infections, including bacteria, mycobacteria, fungi, viruses, and parasites. Although less invasive testing is preferred, surgical biopsy may be necessary to collect diagnostic tissue. Histologic findings, including special stains and immunohistochemistry, can provide a morphologic diagnosis in many cases, which can be further classified by molecular testing. Correlation of molecular, culture, and other laboratory results with histologic findings is essential for an accurate diagnosis, and to minimize false positives from microbial contamination.

Droplet Digital PCR and Immunohistochemistry Techniques to Detect Zika Virus in the Central Nervous System of Mice.

Detection of Zika virus (ZIKV) in the central nervous system (CNS) is a critical step when studying the pathogenesis of the infection in animal models. Both viral load determination and immunohistochemistry (IHC) staining are useful methods to quantitatively and qualitatively characterize viral infections in target tissues. Here, we describe viral RNA load determination by droplet digital PCR as well as protein detection by polymer-based IHC as effective techniques to quantify and localize ZIKV in the CNS of mice.

Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain.

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.

Acute Flaccid Myelitis: A Clinical Review.

Acute flaccid myelitis (AFM) is an emerging disorder primarily affecting children that is characterized by acute flaccid paralysis accompanied by abnormalities of the spinal cord gray matter on magnetic resonance imaging. In most cases, prodromal fever or respiratory symptoms occur, followed by acute-onset flaccid limb weakness. Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected. The clinical manifestations have been described as "polio-like," due to striking similarities to cases of poliomyelitis. The primary site of injury in AFM is the anterior horn cells of the spinal cord, resulting in a motor neuronopathy. Seasonal peaks of cases have occurred in the United States every 2 years since 2012. However, AFM remains a rare disease, which can make it challenging for physicians to recognize and differentiate from other causes of acute flaccid paralysis such as Guillain-Barre syndrome, spinal cord stroke, and transverse myelitis. Epidemiological evidence suggests that AFM is linked to a viral etiology, with nonpolio enteroviruses (in particular enterovirus D68) demonstrating a plausible association. The epidemiology, possible etiological factors, clinical features, differential diagnosis, treatment, and outcomes of AFM are discussed in this review.

Balancing Inflammation and Central Nervous System Homeostasis: T Cell Receptor Signaling in Antiviral Brain TRM Formation and Function.

Tissue-resident memory (TRM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 TRM are predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, TRM are transcriptionally and phenotypically distinct from central-memory T cells (TCM) and effector-memory T cells (TEM). Moreover, TRM differ phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, TRM are governed by a contextual milieu that balances TRM activation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain TRM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)TRM phenotype and function, and discuss the contribution of TRM to promoting protective immune responses in situ while maintaining tissue homeostasis.

Neonatal Herpes Simplex Virus-1 Recurrence with Central Nervous System Disease in Twins after Completion of a Six-Month Course of Suppressive Therapy: Case Report.

Seventeen-day-old twins were hospitalized for neonatal herpes simplex virus 1 (HSV-1) with central nervous system disease and internal capsule and thalamic lesions on magnetic resonance imaging (MRI). They were treated with the usual intravenous (IV) treatment and oral therapy for 6 months. The clinical course was good in both children with negative HSV polymerase chain reaction on completion of IV therapy. The neurological condition recurred in one child with new radiological lesions at 7 months of age, 2 weeks after discontinuation of oral treatment. Cerebral lesions highlighted on the MRI scan are specific to the neonatal period and impact long-term prognosis. The likely genetic predisposition in this case is interesting and requires further investigation. In addition, this case raises questions about the duration of oral acyclovir suppressive therapy.