Search Results (3,492)

Seroprevalence surveys constitute a critical tool for estimating population exposure to infectious agents, particularly during public health emergencies. In the context of the coronavirus disease 2019 (COVID-19) pandemic, such surveys revealed that the circulation of Severe Acute Respiratory Syndrome Coronavirus 2 in Africa had been largely underestimated. The validity of these surveys, however, depends not only on the reliability of diagnostic tests but also on operational conditions, which are frequently challenged by fear, misinformation, and logistical constraints. In the Democratic Republic of the Congo, the National Institute of Biomedical Research conducted two seroprevalence surveys in Kinshasa in 2020 on behalf the project “Appui à la Riposte Africaine à l’Epidémie de COVID-19” (ARIACOV). This study described the challenges encountered and the adaptive strategies employed during these surveys, in order to improve future investigations. The study population comprised 41 eligible field workers who participated in the 2020 ARIACOV seroprevalence surveys in Kinshasa, including 28 interviewers and 13 specimen collectors. Of these, 24 individuals (16 interviewers and 8 specimen collectors) initially confirmed their participation. Ultimately, 15 participants took part in the focus group discussions, comprising 11 interviewers (39.3% of the 28 eligible interviewers) and 4 specimen collectors (30.8% of the 13 eligible specimen collectors). We collected data through two focus groups held in a single session, using a pre-tested semi-structured guide. Discussions were audio-recorded and complemented by observational notes until empirical saturation was achieved. We applied deductive thematic analysis, following Braun and Clarke’s framework, to three predefined domains: transportation, survey procedures, and sample management. The application of systematic manual coding, combined with researcher triangulation, reinforced the rigor and enhanced the credibility of the findings. The findings highlighted community mistrust, driven by rumors, apprehension regarding blood collection, financial suspicions, and inadequate communication. In addition, logistical and transportation challenges significantly constrained survey feasibility. Nonetheless, a range of adaptive strategies were implemented, enabling the successful conduct of the surveys despite the pandemic context and limited resources. The participants’ narratives suggest that strengthening field workers’ training, improving transparency, and working alongside community health workers could contribute to enhance the effectiveness of serological surveys during health crises in resource-constrained environments. Full article

Peptide engineering has emerged as a powerful strategy to optimize naturally occurring peptides. Here, the amphibian skin peptide Hp-1891 from Boana pulchella was selected as a model scaffold to investigate the effects of two complementary engineering approaches, namely site-specific D-amino acid substitution and head-to-tail cyclization. A library of twelve analogues was synthesized by 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis and evaluated for inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), together with antioxidant and hemolytic activities. Circular dichroism spectroscopy and molecular modeling were performed to investigate the structural basis of the observed biological effects. Head-to-tail cyclization consistently enhanced inhibition of AChE, BChE, and Mpro, whereas D-amino acid substitution exerted a greater influence on antioxidant activity and hemolysis. Among the analogue library, c-Hp-d2 emerged as the most promising multifunctional peptide, displaying enhanced inhibition of all three enzymes while maintaining reduced hemolytic activity compared with the native peptide. Structural analyses indicated that cyclization promoted conformational organization, whereas D-amino acid incorporation reduced α-helical propensity. These findings demonstrate that rational peptide engineering effectively reshapes the biological profile of amphibian peptides and highlight head-to-tail cyclization as a versatile strategy for generating multifunctional peptide scaffolds with therapeutic potential. Full article

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), exposed critical gaps in global preparedness for rapidly evolving viral pandemics. Though current antiviral treatments have shown some efficacy in managing COVID-19, substantial limitations, such as inefficient targeted drug delivery, aberrant host immune responses, and inadequate preparedness for future viral pandemics, were also evident. These challenges underscore the urgent need for target-specific, precise and efficient therapeutic strategies to modulate viral entry and immune dysregulation. Extracellular vesicles (EVs), cell-released cargo-carrying nanoscale vesicles, can both facilitate and inhibit viral infection depending on their cargo composition. Thus, endogenous EVs can promote or inhibit COVID-19 pathogenesis by modulating critical pathways, including angiotensin-converting enzyme 2 (ACE2)-mediated viral entry, transmembrane protease serine 2 (TMPRSS2)- dependent spike protein activation, nuclear factor kappa B (NF-κB)-driven inflammatory signaling, and NLRP3 inflammasome activation. In contrast, engineered EVs, such as ACE2-expressing EVs, mesenchymal stem cell-derived EVs and microRNA-enriched EVs, have therapeutic potential as they can facilitate antiviral defense through immune modulation, viral neutralization and suppression of cytokine storm. Moreover, EV-associated nucleic acids, proteins and lipids can act as biomarkers for disease detection and severity stratification. A deeper understanding of EV-virus mechanistic insights can enhance preparedness for similar viral diseases. In this review, we provide a comprehensive analysis of the molecular mechanisms underlying EV-virus interactions highlighting the therapeutic and diagnostic potential of EVs in tackling COVID-19 and future viral pandemics. Full article

Background/Objectives: Host factors angiotensin-converting enzyme 2 (ACE2), transmembrane protease-serine 2 (TMPRSS2), furin paired basic amino acid cleaving enzyme (FURIN), and neuropilin-1 (NRP1) facilitate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry, but it is unclear whether their upper-airway expression after recovery is associated with the severity of the preceding acute illness. We examined the association between post-acute expression of these genes and previous coronavirus disease 2019 (COVID-19) severity. Methods: This multicenter cross-sectional study included 104 adults with polymerase chain reaction (PCR)-confirmed COVID-19 during the first two pandemic waves in Murcia, Spain. Nasal and/or oropharyngeal swabs were collected in the post-acute phase, at a median of 75 days after symptom onset, and transcript levels were quantified by quantitative real-time PCR. Severity was categorized using the World Health Organization (WHO) Clinical Progression Scale, and associations were evaluated using logistic regression adjusted for age, sex, and race/ethnicity. Results: In the primary analyses using continuous expression measures, none of the four genes was significantly associated with severity. In exploratory tertile-based analyses, the intermediate ACE2 tertile (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.05–0.61; p = 0.007) and intermediate NRP1 tertile (OR = 0.29, 95% CI 0.10–0.88; p = 0.030) were associated with lower odds of severe disease; no significant associations were observed for the high tertiles or for FURIN or TMPRSS2. Conclusions: Primary adjusted analyses did not reveal statistically significant associations between post-acute nasal expression of ACE2, TMPRSS2, FURIN, or NRP1 and COVID-19 severity. Because expression was measured after clinical recovery, these associations cannot be interpreted as predictors of acute severity and may instead reflect persistent molecular remodeling after more severe disease; reverse causation cannot be excluded. Longitudinal studies with acute-phase and serial post-acute sampling and healthy controls are needed. Full article

Although persistent neurological sequelae in long COVID are reportedly well associated with neuroinflammation, the underlying regulatory mechanisms remain poorly characterized. Previously, we identified dysregulated microRNA expression, including let-7a-5p, in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike S1-stimulated human microglial cells by RNA sequencing; however, how let-7a-5p regulates the S1-mediated neuroinflammatory processes remains undetermined. In the present study, we examined the functional role of let-7a-5p in alleviating S1-induced microglial inflammation in the CHME3 cell line as well as in human monocyte-derived microglia (MDMi) using a loss- and gain-of-function approach. Functional inhibition of let-7a-5p resulted in mitigating S1-induced inflammatory cytokine release and markers of pyroptosis. Mechanistically, we established SHIP-1 as a direct target of let-7a-5p using luciferase reporter assay validation. Interestingly, we noted upregulated expression of the TLR3 gene alongside TLR2/4 in S1-stimulated microglia. Although we could not establish exactly how TLR3 is stimulated in S1-induced neuroinflammatory processes, using siRNA-mediated inhibition and a pharmacological inhibitor in both CHME3 cells and MDMi, our study certainly provides evidence of TLR3 involvement during S1-induced microglial inflammation, which needs further investigation. Together, these in vitro findings demonstrate that the let-7a-5p/SHIP-1 axis regulates S1-induced inflammatory cascades in CHME3 and MDMi cells, providing mechanistic insight into its role in SARS-CoV-2-associated neuroinflammation and warranting further validation in appropriate in vivo/organoid models. Full article

Coronaviruses comprise a diverse group of enveloped, positive-sense single-stranded RNA viruses capable of causing high morbidity in humans and livestock. The repeated emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 underscores the critical need for broad-spectrum countermeasures. Mounting evidence demonstrates that successful coronavirus infection depends on the manipulation of host cellular pathways governing translation, metabolism, autophagy, and survival. The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that functions via the mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2) to integrate extracellular and intracellular signals. Rather than remaining passive metabolic bystanders, coronaviruses actively exploit and rewrite host PI3K/Akt/mTOR networks to facilitate structural translation, assemble double-membrane replication organelles, suppress autophagic clearance, and reprogram protective innate and adaptive immune landscapes. This review provides a comprehensive synthesis of the molecular mechanisms dictating coronavirus–mTOR interactions across human pathogens and high-impact veterinary models. We detail the clinical consequences of dysregulated mTOR signaling—including immunometabolic perturbations, long-term metabolic memory, and tissue-specific complications—and evaluate the therapeutic potential of allosteric rapalogs, dual ATP-competitive inhibitors, and natural compounds as host-directed platforms designed to complement conventional antiviral regimens and enhance global pandemic preparedness. Full article

Background: This study aims to characterise the clinical and radiological features of Posterior reversible encephalopathy syndrome (PRES) in the context of multisystem inflammatory syndrome in children (MIS-C), consolidating reported cases to aid clinicians in diagnosis, management, and future research. Methods: A systematic review was conducted, adhering to PRISMA guidelines and registered under PROSPERO (CRD420251011869). Four academic databases and grey literature sources were searched up to April 2025. Inclusion criteria were cases with confirmed MIS-C and a diagnosis of PRES supported by compatible clinical and radiological findings or reported by the original investigators when detailed imaging information was unavailable. Results: Sixteen studies encompassing sixteen pediatric cases were identified. The majority were female, with a median age of 9 years. Among patients with available data, hypertension was reported in 8 cases, seizures in 9 cases, and visual disturbances in 4 cases. MRI findings predominantly showed cortical-subcortical hyperintensities in the parieto-occipital, posterior temporal, and frontal lobes. CT was frequently normal. Radiological regression was observed in most follow-up MRIs. Reported management was heterogeneous and variably described, including treatment of hypertension and seizures when present, alongside treatment of MIS-C and other potential precipitating conditions. Favourable clinical outcomes were reported in the published cases in which outcome information was available, with a median length of hospital stay of 26 days (range: 8–45 days). PRES is a rare but clinically important neurological condition reported in children with MIS-C. MRI remains the imaging modality of choice due to its sensitivity in detecting characteristic vasogenic edema, which is often missed on CT. Conclusions: PRES has been reported in a small number of children with MIS-C, but the available evidence is heterogeneous and subject to substantial diagnostic, selection, and publication biases. The relationship between MIS-C and PRES and the prognosis of affected patients still remain to be further elucidated. Full article

Background: Pediatric inflammatory multisystem syndrome (PIMS), also referred to as multisystem inflammatory syndrome in children (MIS-C), is a rare but serious post-infectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection characterized by systemic hyperinflammation and multiorgan involvement. New-onset neurological and psychiatric symptoms have emerged as critical clinical features, occurring in approximately 12–27% of pediatric patients aged 2–15 years (median age, 10 years) and often indicating a more severe disease course. This narrative review aims to provide a comprehensive overview of the current literature regarding the neurological and psychiatric manifestations of PIMS/MIS-C, focusing on epidemiology, pathophysiology, clinical presentation, neuroimaging findings, biomarkers, treatment strategies, and outcomes. Methods: A narrative literature review was conducted to synthesize current evidence on the neurological and psychiatric spectrum of PIMS/MIS-C. Evaluated parameters included clinical presentations ranging from common symptoms (such as headache, encephalopathy, altered mental status, and seizures) to rare complications (such as ischemic stroke, acute disseminated encephalomyelitis, Guillain–Barré syndrome, and cerebral edema), alongside associated psychiatric disturbances, diagnostic findings, and therapeutic approaches. Results: Neurological and psychiatric manifestations significantly impact the clinical trajectory of PIMS/MIS-C. Acute symptoms include headache, encephalopathy, seizures, and psychiatric disturbances like behavioral changes, hallucinations, delirium, anxiety, and sleep disorders. Neuroimaging in many cases reveals reversible lesions of the splenium of the corpus callosum, while electroencephalography typically demonstrates diffuse slowing consistent with encephalopathy. Early recognition and prompt administration of immunomodulatory therapy—primarily intravenous immunoglobulin and corticosteroids—correlate with favorable neurological recovery in the majority of patients. However, current evidence remains largely observational and heterogeneous, precluding definitive causal conclusions regarding this treatment–outcome relationship. Affected children more frequently require intensive care unit admission and remain at risk for persistent cognitive, behavioral, and psychiatric sequelae. Conclusions: Neurological and psychiatric complications in PIMS/MIS-C are clinically significant indicators of disease severity that require vigilant monitoring and early immunomodulatory intervention. Continued multidisciplinary follow-up and prospective studies are essential to elucidate the long-term neurodevelopmental and psychiatric consequences and to optimize therapeutic strategies for these patients. Full article

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in substantial global morbidity and mortality since its emergence in late 2019. This retrospective study aims to determine the comorbidity patterns, co-occurrence networks, and associated demographic factors among 244 deceased COVID-19 cases in Grenada between 2021 and 2022. The prevalence of comorbid conditions varied considerably across diseases. Hypertension was the most frequently observed condition (41%) followed by diabetes (34.8%), and ARDS (27%). Our co-occurrence analysis revealed a densely interconnected core of cardiometabolic and respiratory conditions, particularly involving hypertension, diabetes, and ARDS. Stratified clustering analyses demonstrated that multimorbidity patterns were broadly consistent across gender but differed by age group and vaccination status, with older individuals showing more pronounced clustering of cardiometabolic conditions. Logistic regression analysis further identified age and gender as significant factors associated with the distribution of specific comorbidities, including higher odds of hypertension among older individuals. This study highlights the central role of cardiometabolic diseases and older age in COVID-19 mortality in Grenada in 2021–2022 and underscores the importance of multimorbidity structures rather than isolated conditions. We suggest early identification of high-risk multimorbidity profiles, particularly among older adults, to improve clinical management and preventive strategies during future infectious disease outbreaks. Full article

Airborne viruses are a key driver of infectious disease transmission, highlighting the importance of reliable detection in public health surveillance. As atmospheric viral concentrations are very low, a sampler with a high viral collection efficiency is essential. Although multiple approaches for evaluating collection efficiency have been applied using various samplers, no standardized sampler has yet been developed. We previously developed a wet-type electrostatic precipitator (WT-ESP) and successfully collected severe acute respiratory syndrome coronavirus 2 from the public environment. However, its efficiency for quantitative collection of airborne viruses remains unclear. This study aimed to clarify the collection efficiency of the WT-ESP. We evaluated collection efficiency via two different approaches: direct spray, where virus-containing aerosols were sprayed directly into the WT-ESP inlet, and indirect spray, where aerosols were dispersed into a closed space and then collected using the sampler. The direct spray tests achieved 20.1–50.2% collection efficiency, whereas the indirect spray test achieved an efficiency <12%. These findings highlight that electrostatic precipitation has an advantage of enhancing collection efficiency compared with values reported for impingers in previous studies and provide preliminary insights into the collection efficiencies under direct and indirect spray conditions, providing foundational data that bridge the gap between both methods. Full article

Background/Objectives: Mechanical power (MP) quantifies the energy delivered to the respiratory system during ventilation and serves as a promising marker for ventilator-induced lung injury (VILI). According to its original definition by Gattinoni, MP reflects the energy transferred from the ventilator to the respiratory system under conditions of deep sedation, passive breathing, neuromuscular blockade, and volume-controlled ventilation. Its role in coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome (ARDS) remains under investigation. This systematic review aimed to synthesize the available evidence on the association between MP and VILI, complications related to mechanical ventilation (MV), and mortality in adult patients with COVID-19 undergoing invasive mechanical ventilation (IMV). Methods: A systematic review was conducted using PubMed-MEDLINE (Medical Literature Analysis and Retrieval System Online) for studies published in recent years, focusing on adult COVID-19 patients undergoing IMV. Inclusion criteria centered on studies reporting MP and its association with VILI, complications, or mortality. Ten studies met eligibility criteria after screening 356 retrieved articles. Results: Most included studies were retrospective and observational, encompassing critically ill COVID-19 patients. Elevated MP was correlated with more severe outcomes, including increased 28-day mortality, prolonged MV, and weaning failure. Franck et al. demonstrated strong correlations between MP and driving pressure, elastance, and positive end-expiratory pressure, emphasizing the importance of calculation methods. González-Castro et al. identified a threshold of 17 J/min, above which mortality risk increased. Stalla et al. highlighted that dynamic MP reductions during prone positioning were associated with survival. Registry-based analyses confirmed that both magnitude and cumulative exposure above 18 J/min increased intensive care unit mortality. Novel indices combining MP with oxygenation parameters improved prognostic accuracy. While absolute MP at initiation provided limited predictive value, temporal trends and individual components were strongly linked to VILI. Conclusions: Higher MP has been associated with adverse clinical outcomes in patients with COVID-19 receiving invasive mechanical ventilation, supporting its potential role as a prognostic indicator. Its dynamic assessment, thresholds, and integration with ventilatory strategies such as prone positioning enhance risk stratification and may guide individualized, lung-protective ventilation. Continuous monitoring and standardized calculation are recommended to optimize clinical decision-making. Full article

Background: Legionella pneumophila is a rare but severe cause of community-acquired pneumonia and can lead to acute respiratory distress syndrome (ARDS). Awake prone positioning (APP) has been recognized as an effective adjunct for non-intubated patients with hypoxemic respiratory failure, primarily studied in coronavirus disease 2019 (COVID-19) and other ARDS etiologies. Its application in Legionella-associated ARDS remains poorly documented. Therefore, in this work, we present a case of Legionella-associated ARDS successfully managed with APP, high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), levofloxacin, and corticosteroids. Case presentation: A 62-year-old male with multiple comorbidities, including type 2 diabetes mellitus (T2DM) and a history of coronary artery bypass surgery, presented with a 3-day history of productive cough, exertional dyspnea, and general malaise. Oxygen saturation on admission was 90%, with fever and tachycardia. Inflammatory markers were markedly elevated. Chest computed tomography (CT) revealed extensive bilateral pulmonary infiltrates. Despite a negative urinary Legionella antigen test, sputum polymerase chain reaction (PCR) confirmed Legionella pneumophila on day 2. A Horowitz index of 147 mmHg on day 2 established moderate ARDS. The patient was treated with HFNC oxygen therapy, NIV, and APP for up to 12 h daily. Antibiotic therapy was initiated with amoxicillin/clavulanic acid and clarithromycin, subsequently streamlined to levofloxacin upon microbiological confirmation. Methylprednisolone 40 mg/day was administered for 8 days as adjunctive ARDS therapy. The patient demonstrated gradual clinical and respiratory improvement without requiring endotracheal intubation. Follow-up chest CT on day 7 showed regression of bilateral consolidations and ground-glass opacities (GGOs). The patient was transferred to pulmonary rehabilitation on day 11 and completed antibiotic therapy as an outpatient. Conclusions: This case illustrates the successful use of APP combined with HFNC and NIV alongside standard medical therapies, including appropriate antibiotics and corticosteroids, to avoid intubation in moderate ARDS secondary to Legionella pneumonia. Early initiation of APP may be a valuable strategy in Legionella-associated ARDS in carefully selected patients. Full article

Coronavirus disease 2019 (COVID-19) is increasingly recognized as a multisystem disorder associated with persistent metabolic complications extending beyond the acute phase of infection. Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may disrupt glucose homeostasis through mechanisms involving pancreatic β-cell dysfunction, insulin resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction, and hypoxia-related signalling. This review summarizes current evidence regarding the molecular and cellular mechanisms linking SARS-CoV-2 infection to impaired insulin secretion and post-COVID metabolic disturbances. Particular emphasis is placed on the regulation of insulin secretion, β-cell compensation and failure, oxidative stress, inflammatory signalling, mitochondrial dysfunction, and the development of the post-COVID metabolic phenotype. Emerging evidence indicates that persistent metabolic abnormalities after COVID-19 may range from transient dysglycaemia to new-onset diabetes mellitus and metabolic syndrome. The review also discusses clinical implications, biomarkers, therapeutic perspectives, and unresolved questions regarding the reversibility of post-COVID β-cell dysfunction. A better understanding of the mechanisms underlying post-COVID metabolic dysfunction may improve risk stratification, facilitate early intervention, and support development of targeted therapeutic strategies aimed at preserving β-cell function and long-term metabolic health. Full article

Background and Clinical Significance: Encephalitis is a rare neurological complication associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. In rare cases, focal neuroinflammation can manifest as a mass-like parenchymal lesion, creating profound diagnostic and treatment dilemmas by mimicking primary central nervous system neoplasms. Case Presentation: A 34-year-old female presented with cephalalgia, nausea, confusion, facial palsy, and a new onset of focal impaired awareness seizures (FIAS). Brain magnetic resonance imaging (MRI) revealed a prominent hyperintense lesion within the left temporal lobe with associated vasogenic edema and focal leptomeningeal enhancement highly suspicious of a low-grade glial neoplasm. Although nasopharyngeal RT-PCT was negative, the presence of serum anti-SARS-CoV-2 IgM and IgG suggested recent subclinical SARS-CoV-2 infection. To resolve diagnostic ambiguity and avoid empiric oncological overtreatment, a stereotactic brain biopsy was performed. Histopathology revealed acute neuroinflammation characterized by reactive gliosis, microglial hyperplasia, and perivascular lymphatic cuffing, with no evidence of neoplastic presence. Quantitative tissue RT-PCR confirmed the presence of SARS-CoV-2 (Ct33). Follow-up imaging demonstrated complete resolution of the abnormalities following conservative treatment with corticosteroids and antiepileptics, though mild clinical symptoms persisted for 12 months thereafter. Conclusions: Encephalitis presents a rare yet critical manifestation of SARS-CoV-2. Establishing definitive etiology remains challenging. Stereotactic biopsy is a valuable tool to guide appropriate treatment in cases of ambiguous imaging and clinical findings. Radiographic resolution may precede complete clinical recovery. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes an immune-mediated neurological syndrome, which persists long after infection. Mechanisms for SARS-CoV-2-associated neurological complications are multifactorial, with an increased risk of drug abuse such as methamphetamine (meth). SARS-CoV-2 infection and its viral proteins play pivotal roles in coronavirus disease 2019 (COVID-19)-associated neuroinflammation, which can lead to long COVID. We hypothesize that meth augments activation of the microglial NOD-, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome by the SARS-CoV-2 nucleocapsid (N) protein, resulting in neuroinflammation. To test this hypothesis, we investigated the effect of N-protein and meth on NLRP3 inflammasome activation in primary rat microglial cultures using enzyme-linked immunosorbent assay (ELISA), Reverse Transcription quantitative Polymerase Chain reaction (RT-qPCR), western blot (WB), and immunofluorescence assay (IFA). Our results showed that meth augmented N-protein-induced microglial activation, as evidenced by increased ionized calcium-binding adapter 1 (Iba-1) expression. The addition of meth to the microglial cultures treated with N-protein increased proinflammatory cytokine production. Meth augmentation of N-protein-induced neuroinflammation was further supported by increased inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) production. The effects of meth on N-protein-associated inflammatory responses were significantly attenuated by MCC950, a specific NLRP3 inhibitor. Moreover, meth-associated NLRP3 activation was either blocked by the opioid sigma1-receptor (σ1_-R) inhibitor BD1047 or by σ1R siRNA knockdown. Taken together, these results demonstrated that meth augmented SARS-CoV-2 N-protein-induced neuroinflammation via microglial σ1_-R and the NLRP3 inflammasome, which may underlie the pathogenesis of neurological manifestations in COVID-19, such as long COVID with meth abuse. These results may also underscore the impact of drug abuse on long COVID and provide targets for the development of therapeutic strategies to control the neurological outcomes of long COVID. Full article