Chronological brain lesions after SARS-CoV-2 infection in hACE2-transgenic mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory disease, but it can also affect other organs including the central nervous system. Several animal models have been developed to address different key questions related to Coronavirus Disease 2019 (COVID-19). Wild-type mice are minimally susceptible to certain SARS-CoV-2 lineages (beta and gamma variants), whereas hACE2-transgenic mice succumb to SARS-CoV-2 and develop a fatal neurological disease. In this article, we aimed to chronologically characterize SARS-CoV-2 neuroinvasion and neuropathology. Necropsies were performed at different time points, and the brain and olfactory mucosa were processed for histopathological analysis. SARS-CoV-2 virological assays including immunohistochemistry were performed along with a panel of antibodies to assess neuroinflammation. At 6 to 7 days post inoculation (dpi), brain lesions were characterized by nonsuppurative meningoencephalitis and diffuse astrogliosis and microgliosis. Vasculitis and thrombosis were also present and associated with occasional microhemorrhages and spongiosis. Moreover, there was vacuolar degeneration of virus-infected neurons. At 2 dpi, SARS-CoV-2 immunolabeling was only found in the olfactory mucosa, but at 4 dpi intraneuronal virus immunolabeling had already reached most of the brain areas. Maximal distribution of the virus was observed throughout the brain at 6 to 7 dpi except for the cerebellum, which was mostly spared. Our results suggest an early entry of the virus through the olfactory mucosa and a rapid interneuronal spread of the virus leading to acute encephalitis and neuronal damage in this mouse model.

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Dengue infection in mice inoculated by the intracerebral route: neuropathological effects and identification of target cells for virus replication

Scientific Reports ◽

10.1038/s41598-019-54474-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

J. F. S. Amorim ◽

A. S. Azevedo ◽

S. M. Costa ◽

G. F. Trindade ◽

C. A. Basílio-de-Oliveira ◽

...

Keyword(s):

Dengue Infection ◽

Clinical Manifestations ◽

Target Cells ◽

Histopathological Analysis ◽

Mice Model ◽

Pia Mater ◽

Neurological Morbidity ◽

Life Threatening ◽

The Central Nervous System ◽

The Brain

AbstractDengue is an important arboviral infection, causing a broad range symptom that varies from life-threatening mild illness to severe clinical manifestations. Recent studies reported the impairment of the central nervous system (CNS) after dengue infection, a characteristic previously considered as atypical and underreported. However, little is known about the neuropathology associated to dengue. Since animal models are important tools for helping to understand the dengue pathogenesis, including neurological damages, the aim of this work was to investigate the effects of intracerebral inoculation of a neuroadapted dengue serotype 2 virus (DENV2) in immunocompetent BALB/c mice, mimicking some aspects of the viral encephalitis. Mice presented neurological morbidity after the 7th day post infection. At the same time, histopathological analysis revealed that DENV2 led to damages in the CNS, such as hemorrhage, reactive gliosis, hyperplastic and hypertrophied microglia, astrocyte proliferation, Purkinje neurons retraction and cellular infiltration around vessels in the pia mater and in neuropil. Viral tropism and replication were detected in resident cells of the brain and cerebellum, such as neurons, astrocyte, microglia and oligodendrocytes. Results suggest that this classical mice model might be useful for analyzing the neurotropic effect of DENV with similarities to what occurs in human.

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Aino Virus Antigen in Brain Lesions of a Naturally Aborted Bovine Fetus

Veterinary Pathology ◽

10.1177/030098589803500511 ◽

1998 ◽

Vol 35 (5) ◽

pp. 409-411 ◽

Cited By ~ 15

Author(s):

Y. Noda ◽

Y. Uchinuno ◽

H. Shirakawa ◽

S. Nagasue ◽

N. Nagano ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Brain Lesion ◽

Neutralizing Antibody ◽

Virus Antigen ◽

Brain Lesions ◽

Significant Feature ◽

The Central Nervous System ◽

The Brain

A bovine fetus aborted at 187 days of gestation was serologically and immunohistopathologically examined. Serum and cerebrospinal fluid samples had high titers of virus-neutralizing antibody for Aino virus. A severe necrotizing encephalopathy was noted. Aino virus antigen was demonstrated in neuroglial cells within the brain lesion. The destruction of developing neuronal cells appeared to be a significant feature of the pathogenesis of lesions due to Aino virus infection in the central nervous system.

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Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice

Biochemical Journal ◽

10.1042/bj20021120 ◽

2003 ◽

Vol 370 (2) ◽

pp. 557-566 ◽

Cited By ~ 6

Author(s):

Ying SUN ◽

David P. WITTE ◽

Peng JIN ◽

Gregory A. GRABOWSKI

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Transgenic Mice ◽

Peak Level ◽

Regulatory Elements ◽

Low Level ◽

The Central Nervous System ◽

Flanking Region ◽

The Brain

The expression of prosaposin is temporally and spatially regulated at transcriptional and post-translational levels. Transgenic mice with various 5′-flanking deletions of the prosaposin promoter fused to luciferase (LUC) reporters were used to define its temporal regulatory region. LUC expression in the transgenic mice carrying constructs with 234bp (234LUC), 310bp (310LUC) or 2400bp (2400LUC) of the 5′-flanking region was analysed in the central nervous system and eye throughout development. For 310LUC and 2400LUC, low-level LUC activity was maintained until embryonal day 18 in brain, eye and spinal cord. The peak level of LUC activity was at birth, with return to a plateau (1/3 of peak) throughout adulthood. Deletion of the region that included the retinoic acid-receptor-related orphan receptor (RORα)-binding site and sequence-specific transcription factor (Sp1) cluster sites (44—310bp) suppressed the peak of activity. By comparison, the peak level for 234LUC was shifted 2 weeks into neonatal life in the brain, but not in the eye, and no peak of activity was observed in the spinal cord. The endogenous prosaposin mRNA in eye, spinal cord and cerebellum had low-level expression before birth and continued to increase into adulthood. In cerebrum, the endogenous mRNA showed similar expression profile to constructs 310LUC, 2400LUC and 234LUC, with the peak expression at 1 week and a decreased level in adult. In the brain of the newborn, 2400LUC was highly expressed in the trigeminal ganglion and brain stem regions when compared with the generalized expression pattern for endogenous prosaposin mRNA. These results suggest that the modifiers (RORα- and Sp1-binding sites) residing within 310bp of the 5′-flanking region mediate developmental regulation in the central nervous system and eye. Additional regulatory elements outside the 5′ region of the 2400bp promoter fragment appear to be essential for the physiological control of the prosaposin locus.

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Rift Valley Fever Virus-induced Encephalomyelitis and Hepatitis in Calves

Veterinary Pathology ◽

10.1177/030098589202900602 ◽

1992 ◽

Vol 29 (6) ◽

pp. 495-502 ◽

Cited By ~ 32

Author(s):

M. K. Rippy ◽

M. J. Topper ◽

C. A. Mebus ◽

J. C. Morrill

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Rift Valley ◽

Rift Valley Fever ◽

Positive Staining ◽

Post Inoculation ◽

Valley Fever ◽

Viral Antigens ◽

The Central Nervous System ◽

The Brain

Three calves (Nos. 1, 2 = 7 days old; No. 3 = 21 days old) were inoculated subcutaneously with virulent Rift Valley fever (RVF) virus. All calves became viremic and clinically ill, but the two 7-day-old calves were moribund and were euthanatized subsequently on post-inoculation day (PID) 3. Highest viral titers were measured in the serum, with lesser concentrations in the brain, heart, spleen, and liver of these animals. Viral antigens were detected by immunohistochemical analysis only in the livers, where positive staining was localized in coalescing foci of hepatocellular necrosis. The 21-day-old calf appeared to recover after viremia and pyrexia but became lethargic and ataxic and was euthanatized on PID 9. The calf was no longer viremic, and RVF virus was isolated only from the brain. Microscopic examination of the central nervous system revealed diffuse perivascular infiltrates of lymphocytes and macrophages, multifocal meningitis, and focal areas of neuronal necrosis and aggregates of macrophages, lymphocytes, and neutrophils throughout all regions of the brain and cervical spinal cord. There was positive immunohistochemical staining for viral antigens within the cytoplasm of neurons and glial cells throughout the central nervous system. Thus, RVF virus can cause encephalomyelitis in calves, and the specific virologic diagnosis can be made by immunohistochemical localization of viral antigens in formalin-fixed tissues.

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Lymphocytic meningoencephalomyelitis associated with Myxobolus sp. (Bivalvulidae: Myxozoa) infection in the Amazonian fish Eigenmannia sp. (Sternopygidae: Gymnotiformes)

Revista Brasileira de Parasitologia Veterinária ◽

10.1590/s1984-29612016023 ◽

2016 ◽

Vol 25 (2) ◽

pp. 158-162 ◽

Cited By ~ 1

Author(s):

José Ledamir Sindeaux Neto ◽

Michele Velasco ◽

José Mauro Vianna da Silva ◽

Patricia de Fátima Saco dos Santos ◽

Osimar Sanches ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Histopathological Analysis ◽

Administrative District ◽

Amazon Estuary ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

The Brain ◽

Hematoxylin Eosin

Abstract The genus Myxobolus, parasites that infect fishes, which cause myxobolosis, includes spore organisms belonging to the phylum Myxozoa and represents approximately 36% of all species described for the entire phylum. This study describes lymphocytic meningoencephalomyelitis associated with Myxobolus sp. infection in the brain and spinal cord (the central nervous system, CNS) of Eigenmannia sp., from the Amazon estuary region, in the Administrative District of Outeiro (DAOUT), Belém, Pará, Brazil. In May and June 2015, 40 Eigenmannia sp. specimens were captured from this region and examined. The fish were anesthetized, slaughtered and dissected for sexing (gonad evaluation) and studying parasites and cysts; after diagnosing the presence of the myxozoans using a light microscope, small fragments of the brain and spinal cord were removed for histological processing and Hematoxylin-Eosin and Ziehl-Neelsen staining. Histopathological analysis of the brain and spinal cord, based on histological sections stained with Hematoxylin-Eosin, pronounced and diffuse edema in these tissues, and congestion, degeneration, and focal necrosis of the cerebral cortex. The present study describes lymphocytic meningoencephalomyelitis associated with infection by Myxobolus sp. in the central nervous system of Eigenmannia sp.

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ICAM-1 Participates in the Entry of West Nile Virus into the Central Nervous System

Journal of Virology ◽

10.1128/jvi.02621-07 ◽

2008 ◽

Vol 82 (8) ◽

pp. 4164-4168 ◽

Cited By ~ 51

Author(s):

Jianfeng Dai ◽

Penghua Wang ◽

Fengwei Bai ◽

Terrence Town ◽

Erol Fikrig

Keyword(s):

West Nile Virus ◽

Blood Brain Barrier ◽

Viral Encephalitis ◽

Neuronal Damage ◽

Brain Barrier ◽

Lower Viral Load ◽

West Nile ◽

Blood Brain ◽

The Central Nervous System ◽

The Brain

ABSTRACT Determining how West Nile virus crosses the blood-brain barrier is critical to understanding the pathogenesis of encephalitis. Here, we show that ICAM-1−/− mice are more resistant than control animals to lethal West Nile encephalitis. ICAM-1−/− mice have a lower viral load, reduced leukocyte infiltration, and diminished neuronal damage in the brain compared to control animals. This is associated with decreased blood-brain barrier leakage after viral infection. These data suggest that ICAM-1 plays an important role in West Nile virus neuroinvasion and that targeting ICAM-1 signaling may help control viral encephalitis.

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Neurosyphilis and neuro-AIDS

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0598 ◽

2020 ◽

pp. 6100-6109

Author(s):

Hadi Manji

Keyword(s):

Spinal Cord ◽

Immune Reconstitution ◽

Brain Lesions ◽

Low Grade ◽

Syphilis Infection ◽

Highly Active ◽

Tabes Dorsalis ◽

The Central Nervous System ◽

Inflammatory Syndrome ◽

The Brain

Invasion of the central nervous system occurs early in the course of syphilis infection. Neurosyphilis causes a meningitis, a myeloradiculopathy due to pachymeningitis, gummatous (granulomatous) cord and brain lesions; endarteritis may cause infarction and a low-grade meningoencephalitis affecting the brain results in dementia (general paralysis of the insane) and in the spinal cord, a sensory ataxic syndrome (tabes dorsalis). The introduction of highly active antiretroviral therapies has greatly reduced the frequency of these complications in patients with access to these treatments. However, newer complications are now increasingly recognized such as neurological immune reconstitution inflammatory syndrome, a compartmentalization syndrome (cerebrospinal fluid escape). This chapter looks at these and other important issues regarding the background, diagnosis, treatment, and outlook for neurosyphilis and neuro-AIDS.

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Peripheral Immunosenescence and Central Neuroinflammation: A Dangerous Liaison - A Dietary Approach

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200406123734 ◽

2020 ◽

Vol 20 (9) ◽

pp. 1391-1411 ◽

Cited By ~ 4

Author(s):

Thea Magrone ◽

Manrico Magrone ◽

Matteo A. Russo ◽

Emilio Jirillo

Keyword(s):

Neurodegenerative Diseases ◽

T Regulatory Cells ◽

Neuronal Damage ◽

Age Related ◽

The Central Nervous System ◽

Anti Oxidant ◽

Anti Inflammatory ◽

Neuro Inflammation ◽

Inflammatory Profile ◽

The Brain

Background & Objectives: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS). Aims: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases. Discussion: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer’s disease, Parkinson’s disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics. Conclusion: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.

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Overexpression of human IGF-II mRNA in the brain of transgenic mice modulates IGFBP-2 gene expression in the medulla oblongata

Journal of Endocrinology ◽

10.1677/joe.0.1820445 ◽

2004 ◽

Vol 182 (3) ◽

pp. 445-455 ◽

Cited By ~ 9

Author(s):

CM Reijnders ◽

JG Koster ◽

SC van Buul-Offers

Keyword(s):

Transgenic Mice ◽

Choroid Plexus ◽

Expression Pattern ◽

Medulla Oblongata ◽

Granular Layer ◽

Piriform Cortex ◽

Igf I ◽

The Central Nervous System ◽

The Brain

The insulin-like growth factors, IGF-I and IGF-II, and their binding proteins play an important role in the growth and development of the central nervous system. In the brain, colocalization of IGFs and IGFBPs often occurs, suggesting that IGFBPs can modulate IGF action. In one strain of our human (h)IGF-II transgenic mice, which carry an hIGF-II transgene driven by the H-2Kb promoter, we found overexpression of hIGF-II in the brain, as measured by Northern blot analysis. To clarify the localization and influence of the hIGF-II transgene on different components of the GH-IGF axis in the brain, we studied the expression pattern of the hIGF-II transgene, endogenous IGF-I and IGF-II, and IGFBP-2, -3 and -5 in the brain of prepubertal 4-week-old mice, using nonradioactive in situ hybridization. We found that the hIGF-II transgene is exclusively expressed in neurons of the piriform cortex, the cerebral cortex, the medulla oblongata and the granular layer of the cerebellum. In general, this pattern is comparable to the expression pattern of endogenous IGF-I, with a few exceptions: there is no expression of IGF-I in the granular layer of the cerebellum, whereas the Purkinje cells of the cerebellum and thalamus both express IGF-I but no hIGF-II transgene. This hIGF-II transgene expression pattern contrasts markedly with endogenous IGF-II expression, which is mainly located in nonneuronal cells such as the meninges and choroid plexus, and in some nuclei of the medulla oblongata. The hIGF-II transgene affects neither endogenous IGF-I and IGF-II expression, nor the expression of IGFBP-3, which is located in the choroid plexus. Although the hIGF-II transgene is expressed in neuronal structures similar to IGF-I and IGFBP-5, it is not able to regulate IGFBP-5 expression, as has previously been reported for IGF-I. In the medulla oblongata, the IGFBP-2 expression level showed 10-fold upregulation by the transgene, suggesting a modulating role for IGFBP-2 at the hIGF-II transgene action in this region.

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Preclinical Targeted α- and β−-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies

Cancers ◽

10.3390/cancers12041017 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1017 ◽

Cited By ~ 4

Author(s):

Janik Puttemans ◽

Yana Dekempeneer ◽

Jos L. Eersels ◽

Heleen Hanssens ◽

Pieterjan Debie ◽

...

Keyword(s):

Radionuclide Therapy ◽

Metastatic Cancer ◽

Brain Lesions ◽

Single Domain ◽

Histopathological Analysis ◽

Breast Cancer Patients ◽

Tumor Models ◽

Single Domain Antibody ◽

Her2 Positive ◽

The Brain

HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β−-emitting radionuclides for the detection and treatment of HER2pos brain lesions in a preclinical setting. 2Rs15d was radiolabeled with 111In, 225Ac and 131I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for 131I- and 225Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2pos tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2pos SK-OV-3-Luc-IP1 and HER2pos MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [131I]-2Rs15d and [225Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2pos metastatic cancer.

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