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A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients’ lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.

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BackgroundSepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis.MethodsWe searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words (“microRNA”, “long non-coding RNA”, “circular RNA”, “sepsis” and/or “septic shock”) from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool.ResultsObservational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common.ConclusionsAlthough non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1555-3) contains supplementary material, which is available to authorized users.

Aims Given the concerns of health inequality associated with mental illnesses, we aimed to reveal the extent of which general mortality and life expectancy at birth in people with schizophrenia, bipolar disorder and depressive disorder varied in the 2005 and 2010 nationally representative cohorts in Taiwan. Methods Two nationally representative samples of individuals with schizophrenia, bipolar disorder and depressive disorder were identified from Taiwan's national health insurance database in 2005 and 2010, respectively, and followed-up for consecutive 3 years. The database was linked to nationwide mortality registry to identify causes and date of death. Age-, gender- and cause-specific mortality rates were generated, with the average follow-up period of each age- and gender-band applied as ‘weighting’ for the calculation of expected number of deaths. Age- and gender-standardised mortality ratios (SMRs) were calculated for these 3-year observation periods with Taiwanese general population in 2011/2012 as the standard population. The SMR calculations were then stratified by natural/unnatural causes and major groups of death. Corresponding life expectancies at birth were also calculated by gender, diagnosis of mental disorders and year of cohorts for further elucidation. Results The general differential in mortality rates for people with schizophrenia and bipolar disorder remained wide, revealing an SMR of 3.65 (95% confidence interval (CI): 3.55–3.76) for cohort 2005 and 3.27 (3.18-3.36) for cohort 2010 in schizophrenia, and 2.65 (95% CI: 2.55–2.76) for cohort 2005 and 2.39 (2.31-2.48) for cohort 2010 in bipolar disorder, respectively. The SMRs in people with depression were 1.83 (95% CI: 1.81–1.86) for cohort 2005 and 1.59 (1.57-1.61) for cohort 2010. SMRs due to unnatural causes tended to decrease in people with major mental illnesses over the years, but those due to natural causes remained relatively stable. The life expectancies at birth for schizophrenia, bipolar disorder and depression were all significantly lower than the national norms, specifically showing 14.97–15.50 years of life lost for men and 15.15–15.48 years for women in people with schizophrenia. Conclusions Compared to general population, the differential in mortality rates for people with major mental illnesses persisted substantial. The differential in mortality for unnatural causes of death seemed decreasing over the years, but that due to natural causes remained relatively steady. Regardless of gender, people with schizophrenia, bipolar disorder and depression were shown to have shortened life expectancies compared to general population.