Neurological Manifestations of SARS-CoV-2 Infection and the Role of Complement Activation

Jaffry, Mustafa; Faiz, Iqra; Jaffry, Kazim; Souayah, Nizar

doi:10.17925/usn.2022.18.2.86

Cited by 6 publications

(5 citation statements)

References 102 publications

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“…Therefore, our research raises the possibility that phenothiazines may target additional host receptors or co-receptors, such as dopamine, to modulate cellular entry of SARS-CoV-2. It has been reported that the infection of SARS-CoV-2 is associated with a wide range of neurological manifestations, including encephalopathy, encephalitis, cerebrovascular disease, and headaches [ 49 , 50 ]. Phenothiazines may also be effective in inhibiting SARS-CoV-2 infection in the central nervous system, thus preventing long-term neuronal damage and effectively reducing morbidity.…”

Section: Discussionmentioning

confidence: 99%

Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

Liang,

Xiao,

et al. 2023

Viruses

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Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).

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Section: Discussionmentioning

confidence: 99%

Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

Liang,

Xiao,

et al. 2023

Viruses

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“…Further, the role of complement in the pathogenesis of the Zika virus in the CNS has been shown in mouse models [91]. Recent reports have also highlighted the key role of complement activation in the development of neurological manifestations following SARS-CoV-2 infection [92,93]. Importantly, studies in both animal models and human brain tissue indicate that the impairment of complement regulation may contribute to AD pathogenesis [22,23,26,33,63,[65][66][67].…”

Section: Complement Systemmentioning

confidence: 99%

The Importance of Complement-Mediated Immune Signaling in Alzheimer’s Disease Pathogenesis

Batista,

Khan,

Papavergi

et al. 2024

IJMS

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As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer’s disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.

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“…Dysregulation of the complement system in the CNS contributes to various neurological disorders, including neurodevelopmental disorders such as autism and schizophrenia (Brown, 2012) (Sekar et al, 2022) (Yilmaz et al, 2021), neurodegenerative diseases, diseases associated with disturbances in blood-brain barrier (BBB) functions, etc. Additionally, recent research has demonstrated the critical role of complement cascade in the development of neurological complications of SARS-CoV-2 infection (Jaffry et al, 2022) (M. H. Lee et al, 2022).…”

Section: Complement Proteinsmentioning

confidence: 99%

Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer’s Disease

Ayyubova,

Fazal

2024

Preprint

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Research indicates that brain region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer’s disease (AD) than counts of amyloid plaques, neurofibrillary tangles, and neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of pathology. The complement includes three distinct activation mechanisms, with activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC), leading to cell lysis. Besides pro-inflammatory cytokines, dysregulated complement proteins released by activated microglia bind to amyloid β at synaptic regions and cause microglia to engulf synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating, and that suppression of synaptic engulfment can repair cognitive deficits point to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.

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Neurological Manifestations of SARS-CoV-2 Infection and the Role of Complement Activation

Cited by 6 publications

References 102 publications

Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

The Importance of Complement-Mediated Immune Signaling in Alzheimer’s Disease Pathogenesis

Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer’s Disease

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