ABSTRACT
Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson's disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson's disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with myocardial damage. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been reported to be elevated and to portend worse outcomes among patients hospitalized with coronavirus disease 2019 (COVID-19). The value of NT-proBNP in COVID-19 patients without heart failure (HF) is unclear, and data from the United States are limited. We reviewed the medical records of 304 adults without history of HF admitted to Stony Brook University Hospital, Long Island, NY, from March 1 to April 15, 2020 with documented severe COVID-19 pneumonia requiring high-flow oxygen therapy (non-rebreather mask, Venturi mask with FiO2 >50%, or high-flow nasal cannula). We excluded patients transferred already intubated from outside hospitals and those who were intubated or died within 24h of admission. NT-proBNP was measured with a standard Roche Diagnostics assay with a 5-ng/L limit of detection. Follow-up data were collected until death or hospital discharge or 30 days if still in the hospital by database lock (May 15, 2020). The primary endpoint was all-cause mortality and the secondary endpoint was death or need for intubation. The association of NT-proBNP with the endpoints was evaluated with multivariable Cox regression models. Mean age was 60±17 years;95 (31.2%) of patients were female;156 (51.3%) were White, 103 (33.9%) Hispanic, 22 (7.2%) Black, and 21 (6.9%) Asian;91 (29.9%) had diabetes, 39 (12.8%) coronary artery disease (CAD), and 27 (8.9%) atrial fibrillation (AF);mean body mass index (BMI) was 30.3±6.5 kg/m2. On admission, mean O2 saturation (O2SAT) was 89±8% and median NT-proBNP was 156 ng/L (44-729). After a median of 12 days (8-20), 74 patients (24.3%) died and 59 more (19.4%) were intubated and survived to hospital discharge. Baseline NT-proBNP was strongly associated with mortality. In models adjusting for age, sex, race, diabetes, CAD, AF, BMI, and baseline O2SAT, every log-2 (doubling) of NT-proBNP was associated with 29% higher risk (HR 1.29;95%CI: 1.17-1.43;P<0.001). The association of baseline NT-proBNP with the composite of death or intubation was weaker (HR 1.09;95%CI: 1.01-1.18;P = 025). Among patients hospitalized with severe COVID-19 pneumonia, admission NT-proBNP is a strong predictor of mortality. Elevated NT-proBNP levels may identify a subgroup of patients in need of cardioprotective therapy.