Brain: SARS-CoV-2 Promotes Microglial NLRP3 Inflammasome Activation

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 A new study by researchers from the University of Queensland-Australia and the Australian Infectious Disease Research Centre has found that the SARS-CoV-2 coronavirus promotes microglial NLRP3 inflammasome activation through Spike-ACE2 receptor interaction and this was potentiated in the presence of α-synuclein.

The study findings could help explain the high incidence of severe neurological manifestations in both COVID-19 and Long COVID patients.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.01.11.475947v1

Neuroinflammation is a hallmark of neurodegenerative diseases. A variety of stimuli within the central nervous system (CNS), including pathogens, injury, toxic metabolites, and protein aggregates among others, can lead to the activation of the innate immune response mainly through microglial activation.

When chronically activated, this defence mechanism creates a proinflammatory environment that drives neurodegeneration (1, 2). Microglia are resident populations of macrophages in the CNS that respond to pathogen-associated molecular patterns (PAMPs) and host- or environment-derived danger-associated molecular patterns (DAMPs) to drive innate immune responses and inflammation within the brain.

Recent evidence has highlighted the role of intracellular protein complexes, known as the inflammasomes, in CNS innate immunity.

These complexes mediate the response to PAMPs and DAMPs, leading to the generation of IL-1β, IL-18 and ultimately cellular pyroptosis, which can aid in the elimination of invading pathogens, clearance of damaged cells, and promotion of tissue repair (3).

The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a key inflammasome expressed by microglia (4), and is activated by multiple protein aggregates associated with neurodegenerative disease including α-synuclein in Parkinson’s disease (PD), amyloid-β in Alzheimer’s disease (AD), and TDP43 and SOD1 aggregates in amyotrophic lateral sclerosis (ALS) (5–7).

Microglial NLRP3 inflammasome can also be activated by a variety of pathogenic viruses with neurotropism such as Zika virus (ZIKV) and Japanese Encephalitis virus (JEV) (8, 9). The NLRP3 inflammasome is comprised of the NLRP3 protein, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1.

Activation of NLRP3 is a two-step process; a priming step usually mediated through a Toll-like receptor involves NF-κB-dependent induction of both NLRP3 and pro-IL-1β, whereas the triggering step leads to oligomerisation of NLRP3, recruitment of ASC, and recruitment and activation of caspase-1. Active caspase-1 then cleaves pro-IL-1β and pro-IL-18 into their active forms, and initiates pyroptotic cell death (10).

The hypothesis that viral infections can accelerate neurodegeneration is gaining attention with relevance to the current COVID-19 pandemic (11, 12). It has become clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can invade and affect multiple organs and tissues including the brain (13, 14).

Post-mortem analysis of brains obtained from deceased SARS-CoV-2 patients showed extensive microglial activation with pronounced neuroinflammation in the brainstem (15, 16).

Moreover, accumulating evidence shows that acute and sub-acute neurological complications of SARS-CoV-2 infections are reported in up to 85% of patients not only with severe COVID-19, but also in mildly symptomatic or asymptomatic patients (17, 18).

These manifestations include headache, dizziness, impaired consciousness, encephalopathy, delirium, confusion, seizure, gait difficulties, cerebrovascular events, and post-infectious autoimmunity (19). Peripheral disorders include Guillain-Barre-syndrome, myositis-like muscle injury, and notably, up to 65% of COVID-19 affected patients reported decreased sense of smell or hyposmia (18), which also is a common pre-motor symptom in PD (20).

Additionally, reported cases of PD linked to COVID-19 (21–23), have triggered attention to evaluating SARS-CoV-2 infections and their impact on PD (24, 25). However, the specific mechanism of how SARS-CoV-2 could increase the risk of developing neurological manifestations, and potentially PD, and how this infection could possibly impact synucleinopathy has not been demonstrated.

Here, we used a human monocyte-derived microglia (MDMi) cellular model to assess NLRP3 inflammasome activation in response to SARS-CoV-2, and its spike protein, and the consequences of this exposure in the presence of α-synuclein protein aggregate fibrils. We determined that SARS-CoV-2 isolates, as well as spike protein alone, can both prime and activate the NLRP3 inflammasome in human microglia through NF-κB and ACE2. Microglia exposed to SARS-CoV-2, or its spike protein also potentiated α-synuclein mediated NLRP3 activation, indicating a possible mechanism for COVID-19 and increased vulnerability to developing movement disorders in certain infected individuals.

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