COVID-19 Neuropathology: Evidence for SARS-CoV-2 invasion of Human Brainstem Nuclei

Abstract Neurological manifestations are common in COVID-19, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite some reports of detection of SARS-CoV-2 in the brain and cerebrospinal fluid of patients with COVID-19, it is still unclear whether the virus can infect the central nervous system (CNS), and which neuropathological alterations can be ascribed to viral tropism rather than immune-mediated mechanisms. Available autopsy reports are often conflictual, reporting a heterogeneous spectrum of neuropathological alterations, while viral proteins and RNA were detected only in sparse cells within the brainstem; furthermore, there appears to be no consistent correlation between viral invasion and neuropathological alterations to date. Here, we assess the neuropathological changes occurring in 24 patients who died following a diagnosis of SARS-CoV-2 infection in Italy during the COVID-19 pandemic (from March 2020 to May 2021) and 10 age-matched controls with comparable medical conditions. Aside from a wide spectrum of neuropathological alterations, including astrogliosis, sparse lympho-monocytic infiltrations and several instances of small vessel thromboses, we identified 5 COVID-19 subjects presenting SARS-CoV-2-immunoreactive neurons within the boundaries of the solitary tract nucleus, nucleus ambiguus and substantia nigra in the brainstem. In these subjects, viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation targeting mainly the medulla oblongata and the mesencephalon, and was significantly higher when compared to controls. However, SARS-CoV-2 direct invasion did not appear to correlate with the severity of neuropathological changes. The results of this study support the neuroinvasive potential of SARS-CoV-2 by demonstrating the presence of viral proteins and genome sequences within the human brainstem, but further investigation is required to identify the link between invasion and consequent neuropathological alterations in humans.

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Neural Stem Cells: What Happens When They Go Viral?

Viruses ◽

10.3390/v13081468 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1468

Author(s):

Yashika S. Kamte ◽

Manisha N. Chandwani ◽

Alexa C. Michaels ◽

Lauren A. O’Donnell

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Viral Infections ◽

Wide Spectrum ◽

Cell Types ◽

Developmental Abnormalities ◽

Multipotent Progenitor Cells ◽

The Central Nervous System ◽

Simplex Virus ◽

The Brain

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

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“Corneal Nerves, CD11c+ Dendritic Cells and Their Impact on Ocular Immune Privilege”

Frontiers in Immunology ◽

10.3389/fimmu.2021.701935 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jerry Y. Niederkorn

Keyword(s):

Immune Responses ◽

Inflammatory Diseases ◽

Innate Immune ◽

Immune Privilege ◽

Innate Immune Responses ◽

Regulatory Processes ◽

Immune Mediated ◽

Corneal Nerves ◽

The Central Nervous System ◽

The Brain

The eye and the brain have limited capacities for regeneration and as such, immune-mediated inflammation can produce devastating consequences in the form of neurodegenerative diseases of the central nervous system or blindness as a result of ocular inflammatory diseases such as uveitis. Accordingly, both the eye and the brain are designed to limit immune responses and inflammation – a condition known as “immune privilege”. Immune privilege is sustained by physiological, anatomical, and regulatory processes that conspire to restrict both adaptive and innate immune responses.

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Immovable Object Meets Unstoppable Force? Dialogue Between Resident and Peripheral Myeloid Cells in the Inflamed Brain

Frontiers in Immunology ◽

10.3389/fimmu.2020.600822 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alanna G. Spiteri ◽

Claire L. Wishart ◽

Nicholas J. C. King

Keyword(s):

Myeloid Cells ◽

Cell Types ◽

Brain Parenchyma ◽

Specific Cell ◽

Novel Treatments ◽

Experimental Systems ◽

Immune Mediated ◽

Recent Developments ◽

The Central Nervous System ◽

The Brain

Inflammation of the brain parenchyma is characteristic of neurodegenerative, autoimmune, and neuroinflammatory diseases. During this process, microglia, which populate the embryonic brain and become a permanent sentinel myeloid population, are inexorably joined by peripherally derived monocytes, recruited by the central nervous system. These cells can quickly adopt a morphology and immunophenotype similar to microglia. Both microglia and monocytes have been implicated in inducing, enhancing, and/or maintaining immune-mediated pathology and thus disease progression in a number of neuropathologies. For many years, experimental and analytical systems have failed to differentiate resident microglia from peripherally derived myeloid cells accurately. This has impeded our understanding of their precise functions in, and contributions to, these diseases, and hampered the development of novel treatments that could target specific cell subsets. Over the past decade, microglia have been investigated more intensively in the context of neuroimmunological research, fostering the development of more precise experimental systems. In light of our rapidly growing understanding of these cells, we discuss the differential origins of microglia and peripherally derived myeloid cells in the inflamed brain, with an analysis of the problems resolving these cell types phenotypically and morphologically, and highlight recent developments enabling more precise identification.

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Spread and Replication of and Immune Response to γ134.5-Negative Herpes Simplex Virus Type 1 Vectors in BALB/c Mice

Journal of Virology ◽

10.1128/jvi.78.23.13139-13152.2004 ◽

2004 ◽

Vol 78 (23) ◽

pp. 13139-13152 ◽

Cited By ~ 18

Author(s):

Eeva K. Broberg ◽

Jutta Peltoniemi ◽

Michaela Nygårdas ◽

Tero Vahlberg ◽

Matias Röyttä ◽

...

Keyword(s):

Central Nervous System ◽

Immune Response ◽

Nervous System ◽

Herpes Simplex ◽

Trigeminal Ganglia ◽

Rt Pcr ◽

The Central Nervous System ◽

Simplex Virus ◽

The Brain

ABSTRACT We have previously shown that intracranial infection of herpes simplex virus type 1 (HSV-1) vector R8306 expressing interleukin-4 (IL-4) can abolish symptoms of experimental autoimmune encephalomyelitis, which is used as a model for human multiple sclerosis (Broberg et al., Gene Ther. 8:769-777, 2001). The aim of the current study was to search for means other than intracranial injection to deliver HSV-derived vectors to the central nervous system of mice. We also aimed to study the replication efficiency of these vectors in nervous system tissues and to elucidate the effects of the viruses on the immune response. We studied the spread and replication of the following viruses with deletions in neurovirulence gene γ134.5: R3616, R849 (lacZ transgene), R3659 (alpha-tk), R8306 (murine IL-4 transgene), and R8308 (murine IL-10 transgene). The samples were taken from trigeminal ganglia and brains of BALB/c mice after corneal, intralabial, and intranasal infection, and the viral load was examined by viral culture, HSV DNA PCR, and VP16 reverse transcription (RT)-PCR. The results show that (i) intranasal infection was the most efficient means of spread to the central nervous system (CNS) besides intracranial injection; (ii) the viruses did not grow in the culture from the brain samples, but the viral DNA persisted even until day 21 postinfection; (iii) viral replication, as observed by VP16 mRNA RT-PCR, occurred mainly on days 4 and 7 postinfection in trigeminal ganglia and to a low extent in brain; (iv) R3659, R8306, and R8308 showed reactivation from the trigeminal ganglia in explant cultures; (v) in the brain, the vectors spread to the midbrain more efficiently than to other brain areas; and (vi) the deletions in the R3659 genome significantly limited the ability of this virus to replicate in the nervous system. The immunological studies show that (i) the only recombinant to induce IL-4 mRNA expression in the brain was R8306, the gamma interferon response was very low in the brain for R3659 and R8306, and the IL-23p19 response to R8306 decreased by day 21 postinfection, unlike for the other viruses; (ii) Δγ134.5 HSV vectors modulated the subsets of the splenocytes differently depending on the transgene; (iii) R3659 infection of the nervous system induces expression and production of cytokines from the stimulated splenocytes; and (iv) HSV vectors expressing IL-4 or IL-10 induce expression and production of both of the Th2-type cytokines from splenocytes. We conclude that the intranasal route of infection is a possible means of delivery of Δγ134.5 HSV vectors to the CNS in addition to intracranial infection, although replication in the CNS remains minimal. The DNA of the HSV vectors is able to reside in the brain for at least 3 weeks. The features of the immune response to the vectors must be considered and may be exploited in gene therapy experiments with these vectors.

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Astrocytic and microglial response and histopathological changes in the brain of horses with experimental chronic Trypanosoma evansi infection

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652008000400011 ◽

2008 ◽

Vol 50 (4) ◽

pp. 243-249 ◽

Cited By ~ 9

Author(s):

Karen Regina Lemos ◽

Luiz Carlos Marques ◽

Lucia Padilha Cury Thomaz Aquino ◽

Antonio Carlos Alessi ◽

Rosangela Zacarias Zacarias

Keyword(s):

Nervous System ◽

Mononuclear Cells ◽

Trypanosoma Evansi ◽

Control Group ◽

Reactive Microglia ◽

The Central Nervous System ◽

Males And Females ◽

Microglial Response ◽

The Brain ◽

Experimental Group

This study aimed to characterize astrocytic and microglial response in the central nervous system (CNS) of equines experimentally infected with T. evansi. The experimental group comprised males and females with various degrees of crossbreeding, ages between four and seven years. The animals were inoculated intravenously with 10(6) trypomastigotes of T. evansi originally isolated from a naturally infected dog. All equines inoculated with T. evansi were observed until they presented symptoms of CNS disturbance, characterized by motor incoordination of the pelvic limbs, which occurred 67 days after inoculation (DAI) and 124 DAI. The animals in the control group did not present any clinical symptom and were observed up to the 125th DAI. For this purpose the HE histochemical stain and the avidin biotin peroxidase method was used. Lesions in the CNS of experimentally infected horses were those of a wide spread non suppurative meningoencephalomyelitis.The severity of lesions varied in different parts of the nervous system, reflecting an irregular distribution of inflammatory vascular changes. The infiltration of mononuclear cells was associated with anisomorphic gliosis and reactive microglia was identified. The intensity of the astrocytic response in the CNS of the equines infected by T. evansi characterizes the importance of the performance of these cells in this trypanosomiasis. The characteristic gliosis observed in the animals in this experiment suggests the ability of these cells as mediators of immune response. The parasite, T. evansi, was not identified in the nervous tissues.

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Respiratory viral infections and associated neurological manifestations

Neuroforum ◽

10.1515/nf-2020-0035 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Shirin Hosseini ◽

Kristin Michaelsen-Preusse ◽

Martin Korte

Keyword(s):

Viral Infections ◽

Neurological Diseases ◽

Animal Health ◽

Respiratory Viruses ◽

Target Tissue ◽

Direct Invasion ◽

Spanish Flu ◽

The Central Nervous System ◽

Respiratory Viral Infections ◽

The Brain

Abstract Respiratory viruses as a major threat to human and animal health today are still a leading cause of worldwide severe pandemics. Although the primary target tissue of these viruses is the lung, they can induce immediate or delayed neuropathological manifestations in humans and animals. Already after the Spanish flu (1918/20) evidence accumulated that neurological diseases can be induced by respiratory viral infections as some patients showed parkinsonism, seizures, or dementia. In the recent outbreak of COVID-19 as well patients suffered from headache, dizziness, nausea, or reduced sense of smell and taste suggesting that SARS-CoV2 may affect the central nervous system (CNS). It was shown that different respiratory viral infections can lead to deleterious complications in the CNS by a direct invasion of the virus into the brain and/or indirect pathways via proinflammatory cytokine expression. Therefore, we will discuss in this review mechanisms how the most prevalent respiratory viruses including influenza and coronaviruses in humans can exert long-lasting detrimental effects on the CNS and possible links to the development of neurodegenerative diseases as an enduring consequence.

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HIV-Associated Neurotoxicity: The Interplay of Host and Viral Proteins

Mediators of Inflammation ◽

10.1155/2021/1267041 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Sushama Jadhav ◽

Vijay Nema

Keyword(s):

Chemokine Receptors ◽

Viral Proteins ◽

Neurocognitive Disorder ◽

Asymptomatic Neurocognitive Impairment ◽

Antiretroviral Agents ◽

Aids Epidemic ◽

Current Review ◽

The Central Nervous System ◽

The Brain ◽

Hiv 1

HIV-1 can incite activation of chemokine receptors, inflammatory mediators, and glutamate receptor-mediated excitotoxicity. The mechanisms associated with such immune activation can disrupt neuronal and glial functions. HIV-associated neurocognitive disorder (HAND) is being observed since the beginning of the AIDS epidemic due to a change in the functional integrity of cells from the central nervous system (CNS). Even with the presence of antiretroviral therapy, there is a decline in the functioning of the brain especially movement skills, noticeable swings in mood, and routine performance activities. Under the umbrella of HAND, various symptomatic and asymptomatic conditions are categorized and are on a rise despite the use of newer antiretroviral agents. Due to the use of long-lasting antiretroviral agents, this deadly disease is becoming a manageable chronic condition with the occurrence of asymptomatic neurocognitive impairment (ANI), symptomatic mild neurocognitive disorder, or HIV-associated dementia. In-depth research in the pathogenesis of HIV has focused on various mechanisms involved in neuronal dysfunction and associated toxicities ultimately showcasing the involvement of various pathways. Increasing evidence-based studies have emphasized a need to focus and explore the specific pathways in inflammation-associated neurodegenerative disorders. In the current review, we have highlighted the association of various HIV proteins and neuronal cells with their involvement in various pathways responsible for the development of neurotoxicity.

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Autoimmune diseases of the brain, imaging and clinical review

The Neuroradiology Journal ◽

10.1177/19714009211042879 ◽

2021 ◽

pp. 197140092110428

Author(s):

Ghazal Shadmani ◽

Tyrell J Simkins ◽

Reza Assadsangabi ◽

Michelle Apperson ◽

Lotfi Hacein-Bey ◽

...

Keyword(s):

Critical Role ◽

Daily Practice ◽

Diagnostic Approach ◽

Laboratory Evaluation ◽

Imaging Features ◽

Radiological Findings ◽

Immune Mediated ◽

Clinical Scenarios ◽

The Central Nervous System ◽

The Brain

There is an extensive spectrum of autoimmune entities that can involve the central nervous system, which has expanded with the emergence of new imaging modalities and several clinicopathologic entities. Clinical presentation is usually non-specific, and imaging has a critical role in the workup of these diseases. Immune-mediated diseases of the brain are not common in daily practice for radiologists and, except for a few of them such as multiple sclerosis, there is a vague understanding about differentiating them from each other based on the radiological findings. In this review, we aim to provide a practical diagnostic approach based on the unique radiological findings for each disease. We hope our diagnostic approach will help radiologists expand their basic understanding of the discussed disease entities and narrow the differential diagnosis in specific clinical scenarios. An understanding of unique imaging features of these disorders, along with laboratory evaluation, may enable clinicians to decrease the need for tissue biopsy.

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Brain metastases the challenge of contemporary oncology

Polish Journal of Public Health ◽

10.2478/pjph-2020-0002 ◽

2021 ◽

Vol 130 (1) ◽

pp. 5-7

Author(s):

Łukasz Rams ◽

Katarzyna Świtka ◽

Paulina Kamińska ◽

Bartłomiej Kulesza

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Central Nervous System ◽

Brain Metastases ◽

Wide Spectrum ◽

Small Cell ◽

Small Cell Lung ◽

Anti Cancer ◽

The Central Nervous System ◽

The Brain

AbstractBrain metastases (BM) represent the most common tumours of the central nervous system with ranged between 2.8 and 14.3 per 100.000. Despite advances in the diagnosis and treatment of brain metastases, such as surgery, chemotherapy and radiotherapy only 2.4% of patients will survive 5 years. BM causes a wide spectrum of neurological symptoms, such as hemiparesis, impaired coordination or walking, aphasia, and seizures. Despite the effective treatment of the primary tumor, in many cases, it does not protect against brain metastases. The main source of BMs in adults is, in descending order, non-small cell lung cancer, followed by breast cancer and melanoma and then renal cancer. Some malignancies particularly tend to produce “late” or “delayed” cerebral metastasis years or even decades after the anti-cancer treatment has been accomplished. There is still a need to develop more effective treatments for cancer and metastases to the brain.

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COVID-19 neurological manifestations: a narrative review on the mechanisms, pathogenesis, and clinical management

Research Society and Development ◽

10.33448/rsd-v9i12.10724 ◽

2020 ◽

Vol 9 (12) ◽

pp. e4291210724

Author(s):

Letícia Nunes Campos ◽

Ana Clara Santos Costa ◽

Débora Dantas Nucci Cerqueira ◽

Gabriele Rodrigues Rangel ◽

Isabela Cristina de Farias Andrade ◽

...

Keyword(s):

Nervous System ◽

Viral Entry ◽

Wide Spectrum ◽

Current Evidence ◽

Neurological Manifestations ◽

International Data ◽

The Central Nervous System ◽

Respiratory Conditions ◽

The Brain

Coronaviruses are a large viral family, whose infections are recognized since 1960, varying from the common cold to more critical respiratory conditions. Regarding coronavirus 2019 (COVID-19), a wide spectrum of neurological manifestations among infected patients were reported, raising concerns whether Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had tropism for the central nervous system. To clarify these questions, this bibliographic review was carried out by searching for articles based on national and international data during the period from December 2019 to June 2020. Thus, this review summarizes the current evidence on the transmission routes, focusing on the olfactory bulb and the hematogenic pathways, as well as the direct and indirect pathological mechanisms through which SARS-CoV-2 causes neurological damage. Moreover, clinical, laboratorial, and therapeutic aspects to manage patients with COVID-19 related neurological symptoms are outlined. Finally, development of treatments tackling specific structures and pathways related to viral entry and cardiovascular regulation on the brain are expected, in addition to monitoring of patients affected by the COVID-19 to assess long-term consequences on the nervous system.

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