The Impact of Non-Neurotropic Influenza Strains on the Brain: A Role for Microglial Priming?

Barbosa-Silva, Maria Carolina; Santos, Luís Eduardo; Rangel, Barbara

doi:10.1523/jneurosci.1368-18.2018

Cited by 20 publications

(23 citation statements)

References 22 publications

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“…For the sake of gaining perspective, if we go back to the history of the 1918 "Spanish Flu, " contemporary doctors and researchers observed an intriguing association of encephalitis lethargica (a debilitating nervous disorder in the form of sleep disorder, lethargy, and Parkinson-like symptoms) in flu patients after the recovery. These neurological perturbations could reduce the quality of a patient's life for decades (3,28). Following that, many episodes of the Influenza epidemic and their association with subsequent neurological disorders started convincing researchers that non-neurotropic/peripheral viruses, especially respiratory viruses, can affect the human brain with long-lasting neurological disorders (2).…”

Section: Respiratory Viruses Take the Hematogenous Route Toomentioning

confidence: 99%

“…The common thread among herpes simplex virus (HSV), West Nile virus (WNV), enteroviruses like Poliovirus (PV), Coxsackievirus (CV), Influenza virus (IAV), Measles virus (MV), and especially human respiratory viruses like Coronaviruses (CoV) is that their primary site of infection is not the human Central Nervous System (CNS), yet they are all “Neuropathogenic” and exhibit fatal neurological abnormalities in humans. These viruses infect millions worldwide and cause a spectrum of neurological and psychiatric illnesses ( 1 – 3 ). If we look further into other chronic viral infections - such as Human Immunodeficiency Virus (HIV), John Cunningham Virus (JCV), Herpes Simplex Virus (HSV), Human Herpesvirus 6 (HHV-6), and Human T-lymphotropic virus (HTLV-1) – we realize that peripheral viral infections and the occurrence of neurological sequelae is quite a correlated phenomenon ( 4 – 6 ).…”

Section: Introductionmentioning

confidence: 99%

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Neurological Damage by Coronaviruses: A Catastrophe in the Queue!

Mishra

Banerjea

2020

Front. Immunol.

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Neurological disorders caused by neuroviral infections are an obvious pathogenic manifestation. However, non-neurotropic viruses or peripheral viral infections pose a considerable challenge as their neuropathological manifestations do not emerge because of primary infection. Their secondary or bystander pathologies develop much later, like a syndrome, during and after the recovery of patients from the primary disease. Massive inflammation caused by peripheral viral infections can trigger multiple neurological anomalies. These neurological damages may range from a general cognitive and motor dysfunction up to a wide spectrum of CNS anomalies, such as Acute Necrotizing Hemorrhagic Encephalopathy, Guillain-Barré syndrome, Encephalitis, Meningitis, anxiety, and other audiovisual disabilities. Peripheral viruses like Measles virus, Enteroviruses, Influenza viruses (HIN1 series), SARS-CoV-1, MERS-CoV, and, recently, SARS-CoV-2 are reported to cause various neurological manifestations in patients and are proven to be neuropathogenic even in cellular and animal model systems. This review presents a comprehensive picture of CNS susceptibilities toward these peripheral viral infections and explains some common underlying themes of their neuropathology in the human brain.

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Section: Respiratory Viruses Take the Hematogenous Route Toomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neurological Damage by Coronaviruses: A Catastrophe in the Queue!

Mishra

Banerjea

2020

Front. Immunol.

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“…The dysregulation of microglia has been implicated in the pathophysiology of numerous neurodegenerative disorders [222] . A study of two non-neurotropic strains of the H1N1 influenza virus showed neuroinflammation from cytokine release by activated and primed hippocampal microglial cells [12] . Long-term neuroinflammation persisted beyond the resolution of the acute viral infection [101] .…”

Section: Neuroinflammation and Microglial Cell Dysregulationmentioning

confidence: 99%

“…This modulation is known to occur in response to viral infection. For example, even non-neurotropic viruses that do not invade the brain can cause CNS effects, triggered by a peripheral immune response [12] . Human and animal studies have shown that increases in circulating cytokines can induce typical "sickness behaviors" [50,102,137,246] , including decreases in general activity, exploratory behavior, social and sexual interaction, food and water intake, and preference for sweets (anhedonic behavior), as well as altered sleep and impaired learning.…”

Section: Cytokine Modulation Of the Cnsmentioning

confidence: 99%

A Cytokine-based model for the pathophysiology of Long COVID symptoms

Low¹,

Low²,

Akrami³

2020

Preprint

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The Long COVID group includes patients with mild-to-moderate symptoms, in whom recovery is prolonged, lasting months. Here we propose a model for the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production.In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, and GI and ophthalmic problems can all be attributed to elevated peripheral and central cytokines.There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A post-infectious ME/CFS model involving a dysfunctional peripheral and central cytokine inflammatory response and autoimmunity is emerging. DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

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“…In this scenario, the activated immune response can decrease the neurotrophic (BDNF, NGF) and immunomodulatory (CD200, CXCL1) factors within the hippocampus while increasing the microglial reactivity (Jurgens, Amancherla, and Johnson 2012). Therefore, neurotropic and nonneurotropic in uenza A virus strains might harm the CNS (Barbosa-Silva, Santos, and Rangel 2018). The astrocytes cells following in uenza virus infection induced the ow of several proin ammatory cytokines in addition to the overexpression of genes functioning in synaptic transmission (Lin et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Altered Gene Expression in Human Brain Microvascular Endothelial Cells in Response to the Infection of Influenza H1N1 Virus

Higazy

Lin

Xie

et al. 2021

Preprint

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Influenza viruses are not only causing respiratory illness, but also neurological manifestations were reported following acute viral infection. The Central nervous system (CNS) has a specific defence mechanism against pathogens structured by cerebral microvasculature lined with brain endothelial cells to form the blood-brain barrier (BBB). To investigate the response of human brain microvascular endothelial cells (hBMECs) to the influenza A virus, we inoculated the cells with the A/WSN/33 (H1N1) virus. We then conducted an RNAseq experiment to determine the changes in gene expression levels and the activated disease pathways following infection. The analysis revealed an effective activation of the innate immune defence by inducing the pattern recognition receptors (PRRs). Along with the production of proinflammatory cytokines, we detected an upregulation of interferons and interferon-stimulated genes, such as IFN-β/λ, ISG15, CXCL11, CXCL3, and IL-6, etc. Moreover, infected hBMECs exhibited a disruption in the cytoskeletal structure both on the transcriptomic and cellular levels. We also noted that pathways of neuroactive ligand-receptor interaction, neuroinflammation, and neurodegenerative diseases were noticeably induced together with a predicted activation of the neuroglia. Likewise, a number of genes linked with the mitochondrial structure and function display a significant differential expression. En masse, this data supports that hBMECs could be infected by the influenza A virus, which induces the innate and inflammatory immune response. The results suggest that the influenza virus infection could potentially induce a subsequent aggravation of neurological disorders.

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The Impact of Non-Neurotropic Influenza Strains on the Brain: A Role for Microglial Priming?

Cited by 20 publications

References 22 publications

Neurological Damage by Coronaviruses: A Catastrophe in the Queue!

Neurological Damage by Coronaviruses: A Catastrophe in the Queue!

A Cytokine-based model for the pathophysiology of Long COVID symptoms

Altered Gene Expression in Human Brain Microvascular Endothelial Cells in Response to the Infection of Influenza H1N1 Virus

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