Subject(s)
Cryotherapy , Warts , Humans , Warts/therapy , Cryotherapy/methods , Male , Female , Adult , Treatment Outcome , Young Adult , Middle Aged , AdolescentABSTRACT
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 Parkinsons 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 utilising a model of human monocyte-derived microglia. We identified that SARS-CoV-2 isolates can bind and enter microglia, triggering inflammasome activation in the absence of viral replication. Mechanistically, microglial NLRP3 could be both primed and activated with SARS-CoV-2 spike glycoprotein in a NF-{kappa}B and ACE2-dependent manner. Notably, virus- and spike protein-mediated inflammasome activation in microglia was significantly enhanced in the presence of -synuclein fibrils, which was entirely ablated by NLRP3-inhibition. These results support a possible mechanism of microglia activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinsons disease in certain COVID-19 infected individuals, and a potential therapeutic avenue for intervention. SIGNIFICANCE STATEMENTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) principally affects the lungs, however there is evidence that the virus can also reach the brain and lead to chronic neurological symptoms. In this study, we examined the interaction SARS-CoV-2 with brain immune cells, by using an ex-vivo model of human monocyte-derived microglia. We identified robust activation of the innate immune sensor complex, NLRP3 inflammasome, in cells exposed to SARS-CoV-2. This was dependent on spike protein-ACE2 receptor interaction and was potentiated in the presence of -synuclein. We therefore identify a possible mechanism for SARS-CoV-2 and increased vulnerability to developing neurological dysfunction. These findings support a potential therapeutic avenue for treatment of SARS-CoV-2 driven neurological manifestations, through use of NLRP3 inflammasome or ACE2 inhibitors.
ABSTRACT
SARS-CoV-2 has infected over 160 million people and resulted in more than 3.3 million deaths, and we still face many challenges in the rollout of vaccines. Here, we use the high-density microarray patch to deliver a SARS-CoV-2 spike subunit vaccine directly to the skin. We show the vaccine, dry-coated on the patch is thermostable, and delivery of spike via HD-MAP induced greater cellular and antibody immune responses, with serum able to potently neutralize clinically relevant isolates including those from the B.1.1.7 and B.1.351 lineages. Finally, a single dose of HD-MAP-delivered spike provided complete protection from a lethal virus challenge, demonstrating that HD-MAP delivery of a SARS-CoV-2 vaccine is superior to traditional needle-and-syringe vaccination and has the potential to greatly impact the ongoing COVID-19 pandemic.
ABSTRACT
A recent study proposed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate into the DNA of infected cells. If confirmed, this finding could have significant clinical implications. Here, we applied deep (>50x) long-read Oxford Nanopore Technologies (ONT) sequencing to HEK293T cells infected with SARS-CoV-2, and did not find the virus integrated into the genome. By examining ONT data from separate HEK293T cultivars, we completely resolved 78 L1 insertions arising in vitro in the absence of L1 overexpression systems. ONT sequencing applied to hepatitis B virus (HBV) positive liver cancer tissues located a single HBV insertion. These experiments demonstrate reliable resolution of retrotransposon and exogenous virus insertions via ONT sequencing. That we found no evidence of SARS-CoV-2 integration suggests such events are, at most, extremely rare in vivo, and therefore are unlikely to drive oncogenesis or explain post-recovery detection of the virus.
ABSTRACT
<p><b>INTRODUCTION</b>This study aims to study how the effect of the location of patient collapses from cardiac arrest, in the residential and non-residential areas within Singapore, relates to certain survival outcomes.</p><p><b>MATERIALS AND METHODS</b>A retrospective cohort study of data were done from the Cardiac Arrest and Resuscitation Epidemiology (CARE) project. Out-of- hospital cardiac arrest (OHCA) data from October 2001 to October 2004 (CARE) were used. All patients with OHCA as confirmed by the absence of a pulse, unresponsiveness and apnoea were included. All events had occurred in Singapore. Analysis was performed and expressed in terms of the odds ratio (OR) and the corresponding 95% confidence interval (CI).</p><p><b>RESULTS</b>A total of 2375 cases were used for this analysis. Outcomes for OHCA in residential areas were poorer than in non-residential areas-1638 (68.9%) patients collapsed in residential areas, and 14 (0.9%) survived to discharge. This was significantly less than the 2.7% of patients who survived after collapsing in a non-residential area (OR 0.31 [0.16 - 0.62]). Multivariate logistic regression analysis showed that location alone had no independent effect on survival (adjusted OR 1.13 [0.32 - 4.05]); instead, underlying factors such as bystander CPR (OR 3.67 [1.13 - 11.97]) and initial shockable rhythms (OR 6.78 [1.95 - 23.53]) gave rise to better outcomes.</p><p><b>CONCLUSION</b>Efforts to improve survival from OHCA in residential areas should include increasing CPR by family members, and reducing ambulance response times.</p>
